Triple-negative Breast Cancer Women Research Articles

Abstract PO3-25-06: Expression of CD28, Fas, PD1, and CTLA4 molecules on cellular immune response in the blood peripheral of patients with locally advanced triple-negative breast cancer

Abstract Background: Locally advanced triple-negative breast cancer (TNBC) represents a public health problem in Brazil; its standard treatment consists of neoadjuvant chemotherapy followed by surgical and radiotherapy, with highly variable success rates are depended on access to appropriate cancer treatment, and the type of pathological response. In the last decade, the immune system's role in breast cancer has gained space by demonstrating the favorable impact of lymphocyte tumor infiltrate (TILs) and gene expression of the immune response, especially in tumors with high proliferation rates and negative estrogen receptors. The cellular immune response is regulated by co-stimulatory and co-inhibitory proteins such as CD28, Fas, PD1, and CTLA4 molecules. Methods: This was a longitudinal study with follow-up performed between 2015 and 2017. The study was conducted at the Hospital de Cancer de Pernambuco and Translational Research Laboratory of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Thirty women (18 to 60 years) diagnosed with locally advanced TNBC submitted to neoadjuvant chemotherapy (NAC), and 30 healthy women as a control group were included. The co-stimulatory and co-inhibitory proteins analyses were performed in the peripheral blood of TNBC women before (Pre-NAC) and after NAC (Post-NAC) Results: High levels of CD28+CD3+ T, CD28+CD4+ T, PD1+CD3+ T, and CTLA4+CD3+ T cells in the pathological complete response (pCR) and non-pCR groups compared to the control group (p < 0.05). High levels of Fas+CD4+T cells and PD1+CD8+T cells in the non-pCR compared to the pCR group (p < 0.05). In the paired analysis, significant differences were observed in CD3+T and CD4+T levels with CD28, Fas, and PD1 expression between pre- and post-NAC. Conclusion: Fas+CD4+T and PD1+CD8+T levels in peripheral blood in TNBC are associated with pCR, suggesting potential predictive biomarkers of NAC response. Preliminary results allow us to infer that neoadjuvant chemotherapy modulates the cellular immune response in TNBC women. Citation Format: Marcelo Salgado, Fernando Soares, Denise Viana, Amanda Salgado, Carolina Vasconcelos, Carlos Eduardo Anunciação, Eduardo Salgado, Leuridan Torres. Expression of CD28, Fas, PD1, and CTLA4 molecules on cellular immune response in the blood peripheral of patients with locally advanced 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 PO3-25-06.

Abstract 1284: The effect of Semaphorin 7A on breast cancer metastases and chemoresistance in young women

Abstract Our overall goal is to understand drivers of chemoresistance in triple-negative breast cancer (TNBC) and the mechanisms that contribute to metastatic spread in young women. TNBC is more frequently diagnosed in women aged <40 and confers worse overall and distant-metastatic-free survival. Our lab identified a ß1 integrin-ligand, Semaphorin 7A (SEMA7A), that is increased in TNBC and young women's breast cancer (BC). Our central hypothesis is that SEMA7A is increased in TNBC and signals via ß1-integrin to activate epithelial-to-mesenchymal plasticity (EMP) and chemoresistance. We have incorporated genetically manipulated TNBC cell lines and ex vivo tumor samples to define how SEMA7A expression impacts metastasis and chemoresistance. We have also incorporated our Young Women’s BC Cohort to analyze SEMA7A protein expression in human tumors and mammary epithelial tissue. In this cohort, we found that the normal mammary epithelium and tumors exhibit higher SEMA7A expression in women with postpartum BC, defined as BC diagnosed within 10 years postpartum, who are between 30&39-years-old. This sub-population also has increased tumor-associated lymphatic vessel density, as well as increased lymphovascular invasion and LN involvement. Using a 9-month-old mouse model, which is equivalent to a 35-year-old woman, we have shown that mammary tumor growth and metastasis are increased compared to young 8-week-old mice, which can be mimicked by SEMA7A OE tumors in the young mice; these results suggest that the aged microenvironment can replicate the tumor promotional effects of SEMA7A. Similarly, in orthotopic models, SEMA7A OE cells metastasize more frequently to lymph nodes (LNs) and lungs compared to controls. Additionally, via a tail vein injection, we observe that SEMA7A OE cells survive in circulation, seed the lung, and outgrow faster compared to controls. In vitro, SEMA7A promotes migration and invasion via ß1-integrin signaling. Finally, ex vivo metastatic tumor cells, when compared to parental cells, exhibit evidence of EMP. Namely, prior to dissemination, SEMA7A OE cells are mostly mesenchymal-like. Ex vivo, SEMA7A OE cells from LN metastasis express both epithelial/mesenchymal markers, suggesting a hybrid phenotype and maintenance of an invasive phenotype. Whereas those from the lung are more epithelial, which can be more proliferative. EMP is also known to promote chemoresistance and we have found that SEMA7A OE cells are resistant to caspase-mediated cell death in the presence of paclitaxel, a known chemotherapeutic utilized for TNBC, and have increased activation of pAkt, which can mediate pro-survival phenotypes. Overall, our results suggest that the aged mammary gland and SEMA7A expression can promote metastatic spread and chemoresistance and that these patient populations should be considered for direct and indirect targeting of SEMA7A by novel therapeutics. Citation Format: Kelsey Kines, Sarah Tarullo, Virginia Borges, Traci Lyons. The effect of Semaphorin 7A on breast cancer metastases and chemoresistance in young women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1284.

A retrospective cohort study comparing reconstructive techniques and outcomes in post-mastectomy triple negative breast cancer patients.

Up to 42% of all breast cancer patients undergo post-mastectomy reconstruction, however reconstructive techniques have not been widely studied in patients with triple negative breast cancer (TNBC). Reconstructive complications may delay adjuvant treatments; in TNBC, which inherently carries an increased risk of locoregional recurrence, this can greatly affect oncological outcomes. Therefore, we evaluate factors influencing choice of reconstructive techniques following mastectomy in TNBC patients and assess operative and oncologic safety outcomes. A single institution retrospective chart review identified TNBC patients who underwent post-mastectomy reconstruction between 2010 to 2020. Clinical characteristics collected included demographics, cancer history, reconstructive techniques [autologous-based reconstruction (ABR) vs. implant-based reconstruction (IBR)] and surgical and oncologic outcomes such as complications, recurrence, and mortality. Factors impacting whether patients underwent ABR versus IBR were assessed, as well as differences in outcomes between the two procedures. Statistical significance was defined as P<0.05. During the 10-year period, 52.9% (n=127) of all post-mastectomy TNBC patients (n=240) underwent breast reconstruction, most frequently immediately after mastectomy (97.0%). Most patients underwent IBR compared to ABR (82.4% vs. 14.5%). Patients undergoing ABR were older than IBR patients (54.3 vs. 46.4 years; P=0.040) and had a higher body mass index (BMI; 30.0 vs. 26.1 kg/m2; P=0.007). Patients more often pursued ABR if they had a prior breast cancer history (36.8% vs. 16.7%; P=0.041) or experienced TNBC recurrence (26.3% vs. 9.3%; P=0.034), while primary TNBC patients more often opted for IBR. Reconstructive type did not impact complications (ABR 31.6% vs. IBR 16.8%, P=0.131), recurrence (ABR 15.8% vs. IBR 13.0%, P=0.719), or mortality (ABR 0.0% vs. IBR 6.5%, P=0.593) rates. Factors such as age, BMI, and breast cancer history impacted choice of reconstructive technique among TNBC women. No differences in complications, recurrence, or mortality occur in these high-risk patients regardless of reconstructive technique, highlighting that neither ABR nor IBR is superior in regard to surgical and oncologic safety in post-mastectomy TNBC patients.

Federated learning for predicting histological response to neoadjuvant chemotherapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options. The current standard of care in nonmetastatic settings is neoadjuvant chemotherapy (NACT), but treatment efficacy varies substantially across patients. This heterogeneity is still poorly understood, partly due to the paucity of curated TNBC data. Here we investigate the use of machine learning (ML) leveraging whole-slide images and clinical information to predict, at diagnosis, the histological response to NACT for early TNBC women patients. To overcome the biases of small-scale studies while respecting data privacy, we conducted a multicentric TNBC study using federated learning, in which patient data remain secured behind hospitals' firewalls. We show that local ML models relying on whole-slide images can predict response to NACT but that collaborative training of ML models further improves performance, on par with the best current approaches in which ML models are trained using time-consuming expert annotations. Our ML model is interpretable and is sensitive to specific histological patterns. This proof of concept study, in which federated learning is applied to real-world datasets, paves the way for future biomarker discovery using unprecedentedly large datasets.

Racial and regional disparities of triple negative breast cancer incidence rates in the United States: An analysis of 2011-2019 NPCR and SEER incidence data.

Triple negative breast cancer (TNBC) is a more aggressive subtype resistant to conventional treatments with a poorer prognosis. This study was to update the status of TNBC and the temporal changes of its incidence rate in the US. Women diagnosed with breast cancer during 2011-2019 were obtained from the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology and End Results (SEER) Program SEER*Stat Database which covers the entire population of the US. The TNBC incidence and its temporal trends by race, age, region (state) and disease stage were determined during the period. A total of 238,848 (or 8.8%) TNBC women were diagnosed during the study period. TNBC occurred disproportionally higher in women of Non-Hispanic Black, younger ages, with cancer at a distant stage or poorly/undifferentiated. The age adjusted incidence rate (AAIR) for TNBC in all races decreased from 14.8 per 100,000 in 2011 to 14.0 in 2019 (annual percentage change (APC) = -0.6, P = 0.024). Incidence rates of TNBC significantly decreased with APCs of -0.8 in Non-Hispanic White women, -1.3 in West and -0.7 in Northeastern regions. Women with TNBC at the age of 35-49, 50-59, and 60-69 years, and the disease at the regional stage displayed significantly decreased trends. Among state levels, Mississippi (20.6) and Louisiana (18.9) had the highest, while Utah (9.1) and Montana (9.6) had the lowest AAIRs in 2019. New Hampshire and Indiana had significant and highest decreases, while Louisiana and Arkansas had significant and largest increases in AAIR. In individual races, TNBC displayed disparities in temporal trends among age groups, regions and disease stages. Surprisingly, Non-Hispanic White and Hispanic TNBC women (0-34 years), and Non-Hispanic Black women (≥70 years) during the entire period, as well as Asian or Pacific Islander women in the South region had increased trends between 2011 and 2017. Our study demonstrates an overall decreased trend of TNBC incidence in the past decade. Its incidence displayed disparities among races, age groups, regions and disease stages. Special attention is needed for a heavy burden in Non-Hispanic Black and increased trends in certain groups.

The influence of metabolic factors and ethnicity on breast cancer risk, treatment and survival: The Oslo ethnic breast cancer study

Background Breast cancer risk remains higher in high-income compared with low-income countries. However, it is unclear to what degree metabolic factors influence breast cancer development in women 30 years after immigration from low- to a high-incidence country. Methods Using Cox regression models, we studied the association between pre-diagnostic metabolic factors and breast cancer development, and whether this association varied by ethnicity among 13,802 women participating in the population-based Oslo Ethnic Breast Cancer Study. Ethnic background was assessed and pre-diagnostic metabolic factors (body mass index, waist:hip ratio, serum lipids and blood pressure) were measured. A total of 557 women developed invasive breast cancer, and these women were followed for an additional 7.7 years. Results Among women with an unfavorable metabolic profile, women from south Asia, compared with western European women, had a 2.3 times higher breast cancer risk (HR 2.30, 95% CI 1.18–4.49). Compared with the western European women, the ethnic minority women were more likely to present with triple-negative breast cancer (TNBC) (OR 2.11, 95% CI 0.97–4.61), and less likely to complete all courses of planned taxane treatment (OR 0.26, 95% CI 0.08–0.82). Among TNBC women, above-median triglycerides:HDL-cholesterol (>0.73) levels, compared with below-median triglycerides:HDL-cholesterol (≤0.73) levels, was associated with 2.9 times higher overall mortality (HR 2.88, 95% CI 1.02–8.11). Conclusions Our results support the importance of metabolic factors when balancing breast cancer prevention and disease management among all women, and in particular among non-western women migrating from a breast cancer low-incidence to a high-incidence country.

Correlation between baseline 18F-FDG PET/CT features and pathological complete response after neoadjuvant chemotherapy in early triple negative breast cancer

Aim of the studyTo evaluate correlation between metabolic and textural parameters on baseline 18F-FDG PET/CT and pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer (TNBC). MethodsAll consecutive non-metastatic TNBC women treated by neoadjuvant chemotherapy followed by breast surgery who underwent 18F-FDG PET/CT examination at diagnosis between 2012 and 2018 were retrospectively included. Metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) of the primary tumour and lymph nodes, and textural features (entropy, homogeneity, SRE, LRE, LGZE, HGZE) of the primary tumour were collected. Pathological response was defined according to Sataloff classification. ResultsSeventy-four patients were enrolled. In univariate analysis, metabolic and textural features of the primary breast lesion or metabolic parameters of regional lymph nodes were not predictive of pathological complete response after neoadjuvant chemotherapy. ConclusionMetabolic and textural features of baseline PET/CT do not seem to predict pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer.

Abstract PS11-30: Can metronomic maintenance therapy (MMT) after completion of standard therapy help prevent relapses in patients (Pts) with non-metastatic triple-negative breast cancer (TNBC)

Abstract Background: In-spite of the standard neoadjuvant and adjuvant therapies, stage for stage many more patients with TNBC relapse. This may be because of lack of effective maintenance therapy for TNBC Pts. Recently MMT is being explored to improve outcomes in TNBC. We present a retrospective and prospective analysis of consecutive Pts with TNBC treated at BKLWalawalkarHospital, the rural outreach center of Tata Memorial Centre (India), wherein the outcome of TNBC Pts receiving MMT is being compared to historical control group who did not receive the same. Methods: After standard anthracycline or anthracycline+taxane based therapy, TNBC Pts were either observed (Sept 2003 to March 2011) or received MMT (Nov 2008 to Dec 2018).MMT consisted of 2 phases: initial 12 weeks of daily oral celecoxib (200 mg BD) and cyclophosphamide (50 mg OD) along with 12 doses of weekly IV cisplatin (25 mg/m2). This was followed by 1 year of Phase II maintenance consisting of oral daily metformin (500 mg BD), cyclophosphamide (50 mg OD) along with weekly methotrexate (12 mg/m2).When CAF is the standard regimen 2 phases of maintenance was given , after anthracyclines and taxanes were proved as a standard regimen maintenance was restricted to Phase II considering overlapping toxicities like neuropathy. Results: There were 118 evaluable TNBC Pts. 25 Pts did not receive any MMT.Of the 93 remaining Pts initial 25 received both Phase I &amp; II MMT , 1 patient received only phase I and subsequent 61 Pts have received only Phase II MMT. 6 patients progressed while on initial standard therapy and were not evaluable to assess the effect of MMT .Hence 112 patients are analysed further for outcome.STAGE STRATIFICATION : 8 Pts(6.7%) had AJCC Stage I; 48 Pts(40.6%) had AJCC Stage II; &amp; 62 patients(52.5) had AJCC Stage III disease.MMT and observation groups were comparable with respect to baseline characteristics such as age &amp; stage . Out of 112 patients 87 received MMT and 9 events were noted ,25 did not received MMT and 12 events were noted.EFS by March 2020 is 89.7% in MMT group and 52% in non- MMT group . Median EFS in MMT group is 11.3 yrs ( 9.4 yrs-13.14 yrs 95% CI) , in Off MMT group median EFS 9.2 yrs( 6.4-12 yrs 95% CI).Overall comparison was done by Log rank analysis (Significance 0.006).Median overall survival in OMCT group is 11.8yrs ( 9.9yrs-13.8yrs 95% CI), in non MMT group OS is 9.8yrs( 7.1 yrs-12.6yrs) with significance 0.002.61 patients who received Phase II MMT OS is 13.4 yrs ( 12.5yrs-14.4 yrs 95% CI).By stage stratification in non MMT group 2 patients belong to Stage I , 9patients belongs to Stage II and 14 patients belongs to Stage III. TOXICITIES : MTX 25% dose reduction was done in 7 patients due to Grd2 Mucositis, cyclophosphamide alone was stopped in 1 patient due to grade 3 fatigue, MTX and Cyclophosphamide was stopped in 2 patientsdue grade3 anemia and grade 4 neutropenia, blood transfusion was done in them.Toxicities are much less when compared to CREATEX trial and the follow up duration is very long. Conclusion: Most of the TNBC patients relapse in the early period of follow up and there is an unmet need in the improvement of management. If low dose chemotherapy is given for 1 yr there is a significant improvement in EFS and OS without muchdecrease in QOL.l. This strategy is worthy of being evaluated in definitive randomized trials in TNBC women with large numbers. Citation Format: Kripa Bajaj, Shripad Banavali. Can metronomic maintenance therapy (MMT) after completion of standard therapy help prevent relapses in patients (Pts) with non-metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-30.

Abstract PS3-19: Prognostic value of textural associated with metabolic parameters of baseline 18FDG-PET/CT in early triple-negative breast cancer (TNBC)

Abstract Background : Triple negative breast cancer (TNBC) represents 10-17 % of all diagnosed early breast cancers, occurs more frequently in young women (&amp;lt; 50 years old) and has a poor prognosis. TNBC remains a clinical and therapeutic challenge dealing with a paradox: a high-risk of metastatic relapse despite a high rate of clinical and histological response after neoadjuvant chemotherapy with contrasting but disappointing results of targeted therapies. However, TNBCs are treated as a single entity and due to their phenotypic heterogeneity and various molecular pathogenesis, this subtype has a very different profile in terms of prognosis and response to treatment. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18FDG) is gaining importance for the staging of patients with large or locally advanced breast cancer. TNBCs often show high 18FDG uptake and several studies demonstrate correlations between standard uptake value (SUV) and histoprognostic factors such as grade or KI67%. Recently, a new approach is growing interest in medical imaging: textural analysis. Some studies have shown correlations between metabolic parameters with overall survival (OS) and disease free survival (DFS) in other carcinoma, such as lung and head-and-neck cancers. Few studies analyzed textural features with potentially promising prognostic value that has to be confirmed. The objective of this study is to evaluate the association between metabolic and textural parameters measured at the initial 18FDG-PET/CT, disease-free survival (DFS) and overall survival (OS) in patients with non-metastatic TBNC. Patients and Methods: All consecutive non-metastatic TNBC women who underwent 18FDG-PET/CT at diagnosis between 2012 and 2018 were retrospectively included. Metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) in the primary tumor and lymph nodes and textural features (entropy, homogeneity, SRE, LRE, LGZE, HGZE) in the primary tumor were collected. Regression models were used to assess the correlations between PET parameters and histoprognostic factors. Cox regression models were computed to identify association with DFS and OS. Results : One hundred and eleven patients were enrolled. The median follow-up was 53.6 months. Thirty-six patients experienced relapse and 20 died. Homogeneity was associated with no axillary lymph node involvement and lower grade. Entropy was associated with higher grade, lymph node involvement and inflammatory tumors. SRE was only associated with higher grade. TLG and MTV were highly correlated (r =0.98, 95%CI = 0.97-0.99). TLG, MTV and Entropy of the primary tumor were associated with lower DFS (p = 0.008, p = 0.006, and p = 0.025, respectively) and lower OS (p = 0.002, p = 0.001 and p = 0.046, respectively). In the 50 patients with positive PET axillary lymph nodes, all metabolic parameters except SUVmean were correlated with DFS whereas no correlation was seen with OS. Conclusion: Textural associated with metabolic features of baseline 18FDG-PET/CT add prognosis value interesting to identify high risk group of relapse in early TNBC patients. Citation Format: Clément Bouron, Clara Mathie, Valérie Seegers, Camille Guillerminet, Mario Campone, Olivier Morel, Pascal Jézéquel, Anne Patsouris, Aude Testard. Prognostic value of textural associated with metabolic parameters of baseline 18FDG-PET/CT in early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-19.

Trends in utilization of hypofractionated whole breast irradiation (HF-WBI) in triple negative breast cancer (TNBC): a national cancer database (NCDB) analysis.

We sought to identify trends over time with respect to the use of hypofractionated whole breast irradiation (HF-WBI) in women with triple negative breast cancer (TNBC) in the national cancer database (NCDB). Trends in utilization of HF-WBI in women diagnosed with T1-2N0 TNBC in the NCDB between 2008 and 2013 were analyzed. Case-matched luminal A women were used for comparison. Variables included age, race, year of diagnosis, insurance status, income quartile, receipt of neoadjuvant chemotherapy, and institution (academic vs. community). Chi square, logistic regression, and multivariate analysis was performed. Utilization of HF-WBI among the 53,269 TNBC women identified steadily increased from 4.7% in 2008 to 14.0% in 2013 for women with TNBC compared to luminal A cancer whose utilization increased from 7.3 to 23.3% over the same time frame (p < 0.001). On univariate analysis, HF-WBI was associated with increasing age (p < 0.001), Medicare insurance (p < 0.001), race (p = 0.041), diagnosis after 2011 (p < 0.001), higher income quartile (p < 0.001), and treatment at academic institutions (p < 0.001). On multivariate analysis, age (p < 0.001, OR 1.038 per year), income quartile (p = 0.002, OR 1.061 per increase in quartile), treatment at an academic institution (p < 0.001, OR 1.78) significantly increased use of HF-WBI. Treatment at an academic center and year of diagnosis were most correlated with increased HF-WBI in T1-2N0 TNBC women in the NCDB from 2008 to 2013, followed by increasing age and income. Only 14% of T1-2N0 TNBC women received HF-WBI in 2013. Focus on increased utilization is needed for non-academic centers, lower income, and younger women.

Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens. Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes. In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group. The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.

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.

The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria.

Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca2+ signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca2+ transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca2+ uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.

Current status and novel directions in triple negative breast cancer patients. Risk factors. Role of the platinum-based chemotherapy

Rationale. Breast cancer (BC) has been recognized to be the most common type of cancer in women all over the world. One of the most aggressive subtype of BC is the triple negative breast cancer (TNBC) which is defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) as well as the lack of overexpression of the human epidermal growth factor 2 (HER 2). Aim. As the estrogen and progesterone receptors as well as the expression of HER2 are lacking, a targeted therapy with anti-hormone agents and anti-HER2 cannot be utilized, the therapeutic possibilities for TNBC women are limited. The aim of this review is to present the current scientific data as well as the latest research in TNBC with focus on the risk factors as well as the current role of platinum-based chemotherapeutic agents and their future implications in TNBC treatment. Method. Information about the risk factors associated to TNBC as well as the chemotherapeutic regimens was searched through Pubmed and Medline using controlled vocabulary (e.g. breast cancer) and key words (e.g. neoadjuvant, triple negative, platinum). Systematic reviews, randomized and controlled clinical trials were analyzed. No restrictions regarding date or language were used. Conclusions. TNBC is a complex and heterogeneous disease, divided into many subtypes and with an aggressive evolution. Premenopausal women and African American women are far more likely to develop TNBC. More research is required in order to confirm the association between obesity, BMI, parity, use of oral contraceptives, alcohol and cigarette smoking and TNBC. Randomized clinical trials presented at the San Antonio Symposium suggest that platinum chemotherapy play an important role in the treatment of TNBC, especially early stage TNBC. Tumor-based measures of genomic instability will help to clarify the optimal use and activity of platinum in TNBC. However, it is clear than more epidemiological studies as well as the discovery of novel therapeutic possibilities are mandatory in order to unravel the complexity of this BC subtype, hence offering a chance to women diagnosed with TNBC.

Abstract P5-17-06: Emotional/psychological characteristics of women with triple-negative breast cancer: Do socioeconomic, demographic, and provider variables impact emotional change from diagnosis to post-treatment?

Abstract Purpose: To determine whether women with triple-negative breast cancer (TNBC) experience greater levels of emotional concern from diagnosis through post-treatment compared to women with other breast cancer subtypes. Respondents and Methods: Women diagnosed with breast cancer responded to an 80-question online survey to identify education, information, and support needs. Respondents self-reported their breast cancer subtype and rated the emotions they experienced at diagnosis, during, and after treatment on a scale of "none," "low," "moderate," and "high." The responses of 656 women with TNBC (25.1%) were compared to 1,954 non-TNBC women (74.9%). Differences between TNBC and non-TNBC women were assessed using logistic regression at each time point. Using generalized logistic modeling, differences in score changes were categorized as decreased, same, or increased in relation to cancer subtype and other covariates. Results: At all time points in an unadjusted analysis, TNBC women reported more fear, anxiety, and worry than non-TNBC women, although this finding was only statistically significant for fear and anxiety at diagnosis (high fear: 67% vs. 62%, p=0.046, high anxiety 68% vs. 64%, p=0.046 respectively). Change in emotions between diagnosis and treatment phase was not significantly different between cancer types. Between treatment and post-treatment, women with TNBC were significantly less likely than non-TNBC patients to report a decrease in negative emotion (fear: 58% vs. 66%; anxiety: 54% vs. 65%; worry: 53% vs. 63%, p&amp;lt;0.001 for all). TNBC women with young children were less likely to report a decrease and more likely to report an increase in worry than non-TNBC women (decrease: 61% vs. 70%; increase 8% vs. 4%, p=0.09). A similar pattern was seen in TNBC women with income &amp;lt;$50K annually with respect to fear (decrease: 47.3% vs. 68%, increase 11% vs. 6%, p=0.06). Cancer stage was significantly associated with emotional change. Women with TNBC stage &amp;gt;=2 showed greater increases in negative emotion and lesser decreases in positive emotion than non-TNBC women with similarly staged cancers (p&amp;lt;0.001). Race/ethnicity, age, education, children, living situation, or use of a mental health professional did not influence this relationship. Conclusion: Women with TNBC experience greater fear, anxiety, and worry than women with non-TNBC subtypes at all points from diagnosis though post-treatment. While women with all breast cancer subtypes report a reduction in negative emotion over time from treatment to post-treatment, this change is less profound in TNBC women and appears to be driven nearly entirely by concern about the disease. The marginal effect on change in fear with respect to income may reflect concerns about paying for care, and increased worry in women with small children may reflect concerns about prognosis. Most strikingly, cancer stage was the strongest modifier of emotional change: TNBC women at cancer stage &amp;gt;=2 showed the least decline in negative emotion compared to corresponding non-TNBC women. These data support the development of TNBC-specific interventions focused on these patients’ emotional needs during and after treatment. Citation Format: Kathleen D Swiger, Jocelyn A Sendecki, Janine E Guglielmino, Hope S Rugo, Carey K Anders, Susan M Domchek, Arin Ahlum Hanson, Hayley Dinerman, Catherine Creme Henry. Emotional/psychological characteristics of women with triple-negative breast cancer: Do socioeconomic, demographic, and provider variables impact emotional change from diagnosis to post-treatment? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-17-06.

Abstract P2-11-04: Education and information preferences for women with triple-negative breast cancer: Should personal or medical demographic variables impact program tailoring?

Abstract Purpose: To determine interest in tailored breast cancer education and information among women diagnosed with breast cancer based on personal and medical demographics, including subtype of breast cancer, cancer stage, age, living situation (single, married, children, student, retired), race/ethnicity, or sexual orientation. Respondents and Methods: An 80-question online survey was designed to identify education, information, and support needs among women diagnosed with breast cancer after 2006. Respondents self-identified their breast cancer subtype and selected up to 3 options from a list of preferences about ways in which education and information needs should be tailored. Options were "breast cancer type," "age," "stage," "living situation," "race/ethnicity," "sexual orientation," "no preference," and "other." The responses of 656 women diagnosed with triple-negative breast cancer (TNBC) (25.1%) were compared to those of 1,954 women with other subtypes of breast cancer (74.9%). Logistic regression was used to assess differences in tailoring preferences between TNBC and non-TNBC women. Results: Compared to non-TNBC women, TNBC women had a significantly stronger preference for information tailored to breast cancer subtype (71% vs. 49%, p&amp;lt;0.001) and race/ethnicity (5% vs. 2%, p=0.002) and significantly lesser preference for tailoring based on cancer stage (43% vs. 47%, p=0.004) and living situation (15% vs. 25%, p&amp;lt;0.001). The difference in preference for racial/ethnic tailoring between TNBC and non-TNBC participants may be due to the overall low proportion of non-white respondents to the survey (18.4%) and the higher proportion of non-whites in the TNBC group (18% vs. 11%, p &amp;lt;0.001). There was a significantly different pattern of preference by age group between TNBC and non-TNBC women. TNBC women under 40 had a stronger preference for tailoring to their age group than younger non-TNBC women (age &amp;lt;30, 89% vs. 77%, age 30-39, 74% vs. 62% p=0.02). Across women of all breast cancer subtypes, cancer stage played a role in tailoring preference. Women with higher stage (stage &amp;gt;=2) breast cancer had a stronger preference for tailoring materials based on cancer stage (p&amp;lt;0.001); this pattern did not differ by TNBC status. Conclusion: Education and information tailoring preferences show marked differences by breast cancer subtype. Women with TNBC strongly prefer education and information be tailored to their breast cancer subtype and their race/ethnicity, but are less interested in cancer stage or living situation-specific tailoring. Additionally, younger age influenced preferences in women with TNBC. Across all women, advancing cancer stage influenced preference toward stage-tailored materials. Healthcare providers, cancer centers, and breast cancer organizations should consider developing education and information tailored to the needs of TNBC patients and survivors. Citation Format: Kathleen D Swiger, Jocelyn A Sendecki, Janine E Guglielmino, Hope S Rugo, Carey K Anders, Susan M Domchek, Arin Ahlum Hanson, Hayley Dinerman, Catherine Creme Henry. Education and information preferences for women with triple-negative breast cancer: Should personal or medical demographic variables impact program tailoring? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-11-04.

PCN170 - Estimating the Voi of Pivotal Studies Towards Predictive Biomarkers of High Dose Alkylating Chemotherapy in Triple Negative Breast Cancer

Objectives: To estimate the expected benefits from a pivotal randomised controlled trial of predictive biomarkers for high dose alkylating chemotherapy (HDAC) in triple negative breast cancer (TNBC) and to inform decisions about the design and priority of further studies. Methods: A markov decision model compared treating 40- years old TNBC women with HDAC based on four predictive biomarker strategies: 1) BRCA1-like by MLPA testing; 2) BRCA1-like by aCGH testing, 3) strategy 1 followed by XIST and 53BP1 testing; and 4) strategy 2 followed by XIST and 53BP1 testing, versus treating all patients with standard chemotherapy. A Dutch societal perspective and a 20-year time horizon were used. Input data came from literature and expert opinions. We assessed four primary outcomes: the expected value of (partial) perfect information (EV (P) PI), the expected value of sample information (EVSI) and the expected net benefit of sampling (ENBS) for the ongoing pivotal TNM trial (NCT01057069) and/or potential future studies. Results: The population EVPI was €663 million (M). The EVPPI suggests prioritizing further research towards effectiveness parameters, specifically prevalence and positive predictive value of the biomarkers; response rates in biomarker negative patients and TNBC unclassified patients, which are estimated to collectively have a value of information of circa €630M. The value of further research on transition probabilities is estimated at € 41M, followed by utilities at €34M and costs at €34M. Further information on transition probabilities could be gathered from the TNM trial and that of effectiveness parameters and costs from accompanying studies to this trial, altogether estimated to have an ENBS of €657 M. Conclusions: Further research on predictive biomarkers for HDAC should focus on gathering transition probability data from the current TNM trial, and on accompanying studies to derive data on other effectiveness parameters and costs.

Differential response of neoadjuvant chemotherapy with taxane-carboplatin versus taxane-epirubicin in patients with locally advanced triple-negative breast cancer.

1105 Background: Triple-negative breast cancer (TNBC) may be more sensitive to platinum. The aim of this study was to compare the different pathologic complete response (pCR) in patients with locally advanced TNBC treated with platinum-based neoadjuvant chemotherapy with nonplatinum regimen. Methods: Eligible locally advanced TNBC women received either paclitaxel (or docetaxel)- carboplatin (TC) or paclitaxel (or docetaxel)- epirubicin (TE) q3w for up to 4-6 cycles. The primary end point was the rate of pathological complete response (pCR), defined as the absence of invasive cancer in the breast and axilla at the time of surgery. The second end point was the clinical response rate and recurrence free survival (RFS). Results: In total, 92 patients were enrolled between January 2009 and December 2012. Of these, 43 patients were assigned to TC group, and 49 to TE group. The pCR rate was higher in TC group than in TE group (37.2% versus 16.1%, p=0.032). The clinical response rates were similar in TC and TE gr...

Early assessment with 18F-fluorodeoxyglucose positron emission tomography/computed tomography can help predict the outcome of neoadjuvant chemotherapy in triple negative breast cancer

BackgroundIn patients with triple-negative breast cancer (TNBC), pathology complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This prospective study was designed and powered to investigate the ability of interim 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) to predict pathology outcomes to NAC early during treatment. Patients and methodsConsecutive TNBC women underwent 18FDG-PET/CT at baseline and after two courses of NAC. Maximum standardised uptake value (SUVmax) in the primary tumour and lymph nodes at each examination and the evolution (ΔSUVmax) between the two scans were measured. NAC was continued irrespective of PET results. Correlations between PET parameters and pathology response, and between PET parameters and event-free survival (EFS), were examined. ResultsFifty patients without distant metastases were enroled. At completion of NAC, surgery showed pCR in 19 patients, while 31 had residual tumour. Mean follow-up was 30.3months. Thirteen patients, all with residual tumour, experienced relapse. Of all assessed clinical, biological and PET parameters, ΔSUVmax in the primary tumour was the most predictive of pathology results (p<0.0001; Mann–Whitney-U test) and EFS (p=0.02; log rank test). A threshold of 42% decrease in SUV was identified because it offered the best accuracy in predicting EFS. There were 32 metabolic responders (⩾42% decrease in SUVmax) and 18 non-responders. Within responders, the pCR rate was 59% and the 3-year EFS 77.5%. In non-responders, the pCR rate was 0% and the 3-year EFS 47.1%. ConclusionInterim 18FDG can early predict the inefficacy of NAC in TNBC patients. It shows promise as a potential contributory biomarker in these patients.

Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens. Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes. In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group. The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.