Recurrence In Triple-negative Breast Cancer Patients Research Articles

A novel long non-coding RNA MIR4500HG003 promotes tumor metastasis through miR-483-3p-MMP9 axis in triple-negative breast cancer

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.

Abstract 4925: Spatial heterogeneity of tumor boundary in mammograms is prognostic of recurrence in triple negative breast cancer (TNBC)

Abstract Introduction: Despite standard-of-care therapies, at least 25% of all TNBC patients will develop recurrence or metastasis within 3-5 years and die due to breast cancer. Early prediction of recurrence in TNBC patients from clinical mammograms would allow more aggressive intervention for higher risk patients. The tumor boundary represents the heterogeneous invasive front where malignant cells interface extracellular matrix (ECM) and contribute to invasion. In this study, we investigated role of the irregular infiltration of the normal tissue by tumor in heterogeneity of radiomics features at the boundary of the tumor. Method: Surgically treated patients with pathologically confirmed diagnosis of TNBC of any tumor size were included. All cases had node negative status and were treated with adjuvant chemotherapy. Patients with node positive or metastatic TNBCs at diagnosis, receiving neo-adjuvant chemotherapy or non-chemo regimens were excluded. Manually segmented breast lesions in mammograms from a cohort of 29 patients with 5-year outcomes were used to automatically determine the tumor boundary as a zone of 1 mm from both intra-tumoral and peritumoral regions in concordance with prior studies. Over 2000 radiomics features from the tumor boundary and the central regions of the tumor were extracted to quantify heterogeneity, obscure margins, spiculations, texture, breast fat percentage, shape, and size of the tumor. Recursive feature elimination using random forest classifier was used to reduce feature dimensionality to prevent over-fitting and predict recurrence in TNBC patients. Results: We observed that tumor boundary heterogeneity as quantified by continuous gradient magnitude features at pixel level was significantly better at predicting lethality for TNBC patients when compared to usual radiomic features (gradient, texture, and shape features) extracted from the entire tumor, as done in prior radiomics analyses. Continuous gradient magnitude features quantifying spatial heterogeneity of the tumor boundary were found to be superior to texture features in providing estimation of local changes in pixel-level heterogeneity. In a three-fold validation framework, continuous gradient features were associated with a mean AUC of 0.82 (std 0.17) and better differentiated patient lethality risk as compared to gradient, texture, and shape features of the entire tumor (mean AUC of 0.27 (std 0.11)). Conclusions: To the best of our knowledge, this is the first time that heterogeneity features of a tumor quantified by continuous gradient magnitude features from tumor boundary, as observed in routine clinical mammograms, have been shown to predict TNBC lethality. This model will be validated in a larger cohort in future studies. Citation Format: Soumya Ghose, Cynthia Davis, Sanghee Cho, Yesim Polar, Fiona Ginty, Sunil Badve. Spatial heterogeneity of tumor boundary in mammograms is prognostic of recurrence in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4925.

Targeting molecular cross-talk between tumor cells and tumor associated macrophage as therapeutic strategy in triple negative breast cancer

Triple-negative Breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks expression for ER/PR/Her2 receptors and is associated with aggressive disease pathogenesis and the worst prognosis among other subtypes of BC. Accumulating evidence-based studies indicate the high immunogenic ability of TNBC tumors and the applicability of immunotherapeutic strategies to overcome therapy resistance and tumor recurrence in TNBC patients. However, not all TNBC patients respond equally well to current immunotherapies that mainly target the adaptive immune system for tumor rejection. Recent studies are contemplating the efficacy of tumor-associated macrophage (TAM) targeted therapies since these subpopulations of cells comprise one of the major components of tumor-infiltrating immune cells (TIIs) in the TNBC tumor microenvironment (TME) and play an essential role in priming the adaptive immune response mediators towards both antitumorigenic and pro-tumorigenic response facilitated by intercellular cross-talk between tumor cells and TAM populations present within TNBC-TME. The present review discusses these molecular mechanisms and their consequence on the progression of TNBC tumors. Also, the therapeutic strategies targeting candidate genes/pathways involved in molecular cross-talk between TAM-TNBC cells and their impact on the development and progression of TNBC tumors are also discussed.

Prognostic Capability of TNBC 3-Gene Score among Triple-Negative Breast Cancer Subtypes.

Simple SummaryIn this study we evaluated the prognostic capability of the 3-gene score in the molecular subtypes of triple negative breast cancer and found that the score was able to predict the risk of distant recurrence in the immunomodulatory and mesenchymal stem-like subtypes. Additionally, a low 3-gene score was related to a high level of tumor-infiltrating lymphocytes. Our findings suggest that the prognostic capability of the 3-gene score is associated to tumor-infiltrating components.Background: Triple-negative breast cancer (TNBC) is a complex and molecularly heterogeneous entity, with the poorest outcome compared with other breast cancer subtypes. Previously, we developed a TNBC 3-gene score with a significant prognostic capability. This study aims to test the 3-gene score in the different TNBC subtypes. Methods: Data from 204 TNBC patients treated with neoadjuvant chemotherapy were retrieved from public datasets and pooled (GSE25066, GSE58812, and GSE16446). After removing batch effects, cases were classified into Lehman’s TNBC subtypes and then the TNBC 3-gene score was used to evaluate the risk of distant recurrence in each subgroup. In addition, the association with tumor-infiltrating lymphocyte (TILs) levels was evaluated in a retrospective group of 72 TNBC cases. Results: The TNBC 3-gene score was able to discriminate patients with different risks within the pooled cohort (HR = 2.41 for high vs. low risk; 95%CI: 1.50–3.86). The score showed predictive capability in the immunomodulatory subtype (HR = 4.16; 95%CI: 1.63–10.60) and in the mesenchymal stem-like subtype (HR = 18.76; 95%CI: 1.68–208.97). In the basal-like 1, basal-like-2, and mesenchymal subtypes, the observed differential risk patterns showed no statistical significance. The score had poor predictive capability in the luminal androgen receptor subtype (p = 0.765). In addition, a low TNBC 3-gene score was related to a high level of TIL infiltration (p < 0.001). Conclusions: The TNBC 3-gene score is able to predict the risk of distant recurrence in TNBC patients, specifically in the immunomodulatory and mesenchymal stem-like subtype. Despite a small sample size in each subgroup, an improved prognostic capability was seen in TNBC subtypes with tumor-infiltrating components.

A prognostic model for distant recurrence-free survival in triple-negative breast cancer (TNBC) and the outcomes of initiation of adjuvant chemotherapy in the risk of relapse.

530 Background: TNBC is a highly complex, heterogenous disease associated with poor outcomes, high incidence of distant metastases, and limited treatment options. With the purpose of identify patients at different risk of distant recurrence, we developed a prognostic model using clinicopathological characteristics that contribute to the risk of recurrence in TNBC patients and also evaluate its influence in the time of beginning of adjuvant therapy. Methods: We retrospectively analyzed 687 TNBC patients who received adjuvant chemotherapy between January 2000 to December 2014 at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru). The database was randomly divided into two groups to create a discovery set (n = 344) and a validation set (n = 343). Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for distant recurrence-free survival (DRFS). We developed a linear risk score based on clinicopathologic characteristics. Under STEPP methodology we classified patients at high, intermediate or low-risk of distant recurrence and the absolute treatment effects of time to initiation of chemotherapy (TTC, ≤ 30 vs &gt; 30 days) through risk subgroups was estimated. Results: The median of follow-up was 9.90 years. In total, 31.0% (n = 213/687) relapses were registered. Variables associated with DRFS in the multivariate analysis were: age, T-staging, and N-staging. A tumor staging of T3-T4 vs. T1/T2 (HR = 2.92, 95%CI: 1.39 - 6.17), followed by the number of positive lymph nodes (N2-N3 vs N0/N1; HR = 2.78, 95%CI: 1.74 - 4.45) and an older age (≥ 60 years vs. ≤ 40/41-59, HR = 2.66, 95%CI: 1.46 - 4.88) were the clinicopathologic characteristics contributing to a higher risk score according to the 3-variable model. Also, 3 risk groups were identified and corroborated in the validation group. In the discovery set, patients with a TTC &gt; 30 days experienced an overall decreased of 17.5% (95%CI: 6.7 - 28.3) in 10-year DFRS vs. those who initiated adjuvant therapy before 30 days. The impact of TTC &gt; 30 days was higher in patients classified as high-risk (Decreased 10-year DFRS: 53.3 ± 28.8 %), similar findings were found in the validation set. Conclusions: A prognostic model based in clinicopathological characteristics (age, pT and pN), was able to classify TNBC patients’ candidates to adjuvant chemotherapy in 3 prognostics groups. We identified a subgroup of patients in which delaying of adjuvant chemotherapy (&gt; 30 days) confers very high-risk of relapse.

Genetic Association of CYP1B1 4326 C>G Polymorphism with Disease-Free Survival in TNBC Patients Undergoing TAC Chemotherapy Regimen.

Background:Triple negative breast cancer (TNBC) which is treated with taxane, adriamycin and cyclophosphamide (TAC) chemotherapy regimen show variation in treatment response. CYP1B1 4326 C>G polymorphism has been implicated in contributing to the differences in treatment response in various types of cancers. Aim:The objective of the present study was to investigate whether this polymorphism modulate the risk of disease recurrence in TNBC patients undergoing TAC chemotherapy regimen. Methods:Blood samples of 76 immunohistochemistry confirmed TNBC patients were recruited. The genotyping of CYP1B1 4326 C>G polymorphism was carried out using PCR-RFLP technique. The genotype patterns were categorized into homozygous wildtype, heterozygous and homozygous variant. Kaplan-Meier analysis followed by Cox proportional hazard regression model were performed to evaluate the TNBC patients’ recurrence risk. Results:Out of 76 TNBC patients, 25 (33.0%) showed disease recurrence after one-year evaluation. Kaplan Meier analysis showed that TNBC patients who are carriers of CYP1B1 4326 GG variant genotypes (37.0%) had a significantly lower probability of disease-free rates as compared to TNBC patients who are carriers of CYP1B1 4326 CC/CG genotypes (71.0%). Univariate and multivariate Cox analysis demonstrated that TNBC patients who carried CYP1B1 4326 GG variant genotype had a significantly higher risk of recurrence with HR: 2.50 and HR: 4.18 respectively, even after adjustment as compared to TNBC patients who were carriers of CYP1B1 4326 CC and CG genotypes. Conclusion:Our results demonstrate the potential use of CYP1B1 4325 GG variant genotype as a candidate biomarker in predicting risk of recurrence in TNBC patients undergoing TAC chemotherapy regimen.

Abstract P1-10-09: The MHCII immune activation assay is prognostic for disease free survival in basal-like TNBC breast cancer patients in the GEICAM/9906 clinical trial

Abstract Background: Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) recur after standard treatment, while the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously developed and validated an MHCII Immune Activation assay, which measures a gene expression signature that includes the major histocompatibility complex class II (MHCII) pathway genes and markers of activated tumor infiltrating lymphocytes. The MHCII Immune Activation assay was recently shown to accurately assess the risk of recurrence in Basal-like TNBC patients using FFPE tissues from an institutional cohort. A limitation of the previous study is that the patients’ treatment regimens in the institutional cohort were heterogeneous. The goal of this study was to determine if the MHCII Immune Activation assay can accurately assess the DFS in Basal-like TNBC patients who received uniform chemotherapy regimens in the context of a randomized clinical trial. Methods: The MHCII Immune Activation assay was applied to RNA isolated from 60 Basal-like TNBC FFPE specimens from the GEICAM/9906 clinical trial, a multicenter randomized phase III study evaluating adjuvant chemotherapy in node-positive operable BC patients. Thirty nine (65%) of the patients were treated with fluorouracil, epirubicin, and cyclophosphamide (FEC), and 21 (35%) patients received FEC followed by paclitaxel (FEC-P) (median follow-up 9.7 years). The MHCII Immune Activation Score was calculated from the assay using methods described previously, and patients were categorized into a High Risk of Recurrence (High ROR) group using pre-specified thresholds. The association between the MHCII Immune Activation Score and DFS was assessed using Kaplan-Meier analysis and cox proportional hazards models. Results: Across both arms, 32/60 (53.3%) patients were classified into the High ROR group based on their Low MHCII Immune Activation Scores. Patients in the High ROR group had significantly shorter DFS (Hazard Ratio (HR)=2.9 (CI95%:1.27-6.66), p-value=0.0081). Cox proportional hazard regression of the log10 transformed MHCII Immune Activation Score confirmed that MHCII Immune Activation Score is significantly associated with DFS (Wald Test p=0.0127). In the FEC arm, there were 22/39 (56.41%) patients classified into the High ROR group (Low MHCII Immune Activation Score). Patients in the High ROR group in the FEC arm showed a trend toward shorter DFS (HR=1.99 (CI95%:0.74-5.31)), but it was not significant (p-value=0.1595). In the FEC-P arm, there were 10/21 (47.62%) patients classified into the High ROR group (Low MHCII Immune Activation Score). Patients in the High ROR group in the FEC-P arm had significantly shorter DFS (HR=6.28 (CI95%:1.28-30.73), p-value=0.0111). Larger cohorts will be needed to confirm if the association between DFS and MHCII Immune Activation Score is stronger when patients are treated with chemotherapy regimens that include paclitaxel. Conclusions: The MHCII Immune Activation assay can be applied to RNA from FFPE tumor specimens to assess risk of recurrence in TNBC patients. The MHCII Immune Activation Score is associated with risk of recurrence in TNBC patients treated with uniform adjuvant chemotherapy regimens. Citation Format: Miguel Martín, Katherine L Updike, Alvaro Rodríguez-Lescure, Lourdes Calvo, Jesús Herranz, Nuria Martín, Philip S Bernard, Katherine E Varley. The MHCII immune activation assay is prognostic for disease free survival in basal-like TNBC breast cancer patients in the GEICAM/9906 clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-09.

A Multigene Assay Determines Risk of Recurrence in Patients with Triple-Negative Breast Cancer.

Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) recur after standard treatment, whereas the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously determined that TNBC patients with MHC class II (MHCII) pathway expression in their tumors experienced significantly longer DFS. To translate this discovery into a clinical test, we developed an MHCII Immune Activation assay, which measures expression of 36 genes using NanoString technology. Preanalytical testing confirmed that the assay is accurate and reproducible in formalin-fixed paraffin-embedded (FFPE) tumor specimens. The assay measurements were concordant with RNA-seq, MHCII protein expression, and tumor-infiltrating lymphocyte counts. In a training set of 44 primary TNBC tumors, the MHCII Immune Activation Score was significantly associated with longer DFS (HR = 0.17; P = 0.015). In an independent validation cohort of 56 primary FFPE TNBC tumors, the Immune Activation Score was significantly associated with longer DFS (HR = 0.19; P = 0.011) independent of clinical stage. An Immune Activation Score threshold for identifying patients with very low risk of relapse in the training set provided 100% specificity in the validation cohort. The assay format enables adoption as a standardized clinical prognostic test for identifying TNBC patients with a low risk of recurrence. Correlative data support future studies to determine if the assay can identify patients in whom chemotherapy can be safely deescalated and patients likely to respond to immunotherapy. SIGNIFICANCE: The MHCII Immune Activation assay identifies TNBC patients with a low risk of recurrence, addressing a critical need for prognostic biomarker tests that enable precision medicine for TNBC patients.

Micro-RNA Expression Profiling in Malaysian Triple-Negative Breast Cancer Patients: Impact on Recurrence Prediction

Background: Triple negative breast cancer (TNBC) is characterized by its biologic aggressiveness, worse prognosis and lack of therapeutic targets. Due to high probability of tumor recurrence and also due to lack of available targeted therapies, TNBC patients are treated with standard chemotherapy using TAC [taxane (T), adriamycin (A) and cytoxan (C)] chemotherapy regimen. However, TNBC patients present significant interindividual differences of treatment efficacy. Drug resistance and recurrence remains major clinical obstacles to successful treatment in many TNBC patients. This warrants the need for early identification of TNBC patients who are likely to be chemosensitive and those who have high recurrence risk. TNBC may have specific molecular features that could be possible targets for new biologic targeted drugs. microRNAs (miRNAs) which are aberrantly expressed in tumors, can target and modulate key genes involved in TNBC chemotherapy. Aberrant microRNA expression is strongly implicated in anticancer drug resistance phenotype and hence, miRNAs appear to be promising candidates for response and recurrence prediction. Aim: To investigate the expression profile of few candidate miRNAs (miR-21, miR-27b, miR-34a, miR-182, miR-200c and miR-451) in tumourous and nontumourous tissues in Malaysian TNBC patients and their utility as predictive markers of recurrence in TNBC patients. Methods: Malaysian TNBC patients who had undergone TAC chemotherapy regimen at Hospital Universiti Sains Malaysia were identified and the clinicopathological variables were recorded. Total RNA from cancerous and adjacent noncancerous tissues of FFPE samples from 41 patients were isolated, transcribed and preamplified. The expression of selected miRNAs (miR-21, miR-27b, miR-34a, miR-182, miR-200c and miR-451) were quantified using quantitative real-time PCR (qRT-PCR). The miRNAs expression was categorized into two groups based on upregulation and downregulation. The disease outcome of the patients were evaluated after completion of chemotherapy. Disease-free survival (DFS) analysis using Kaplan-Meier method followed by univariate and multivariate Cox's regression analysis were performed to investigate the impact of these candidate miRNAs on recurrence prediction. Results: The relative expressions of miR-27b and miR-451 were found to be significantly lower in cancerous as compared with normal adjacent tissues of TNBC patients. Multivariate Cox's regression analysis demonstrated that medullary and metaplastic tumor subtypes and positive axillary lymph nodes significantly increased the risk of recurrence in TNBC patients. Downregulated expression of miR-21 and upregulated expression of miR-182 were found to be associated with risk of recurrence in TNBC patients. Conclusion: Tumor subtypes, positive axillary lymph nodes as well as expression profiles of miR-21 and miR-182 could be useful as predictive biomarkers of recurrence in TNBC patients.

Micro-RNA Expression Profiling in Malaysian Triple-Negative Breast Cancer Patients: Impact on Recurrence Prediction

Background: Triple negative breast cancer (TNBC) is characterized by its biologic aggressiveness, worse prognosis and lack of therapeutic targets. Due to high probability of tumor recurrence and also due to lack of available targeted therapies, TNBC patients are treated with standard chemotherapy using TAC [taxane (T), adriamycin (A) and cytoxan (C)] chemotherapy regimen. However, TNBC patients present significant interindividual differences of treatment efficacy. Drug resistance and recurrence remains major clinical obstacles to successful treatment in many TNBC patients. This warrants the need for early identification of TNBC patients who are likely to be chemosensitive and those who have high recurrence risk. TNBC may have specific molecular features that could be possible targets for new biologic targeted drugs. microRNAs (miRNAs) which are aberrantly expressed in tumors, can target and modulate key genes involved in TNBC chemotherapy. Aberrant microRNA expression is strongly implicated in anticancer drug resistance phenotype and hence, miRNAs appear to be promising candidates for response and recurrence prediction. Aim: To investigate the expression profile of few candidate miRNAs (miR-21, miR-27b, miR-34a, miR-182, miR-200c and miR-451) in tumourous and nontumourous tissues in Malaysian TNBC patients and their utility as predictive markers of recurrence in TNBC patients. Methods: Malaysian TNBC patients who had undergone TAC chemotherapy regimen at Hospital Universiti Sains Malaysia were identified and the clinicopathological variables were recorded. Total RNA from cancerous and adjacent noncancerous tissues of FFPE samples from 41 patients were isolated, transcribed and preamplified. The expression of selected miRNAs (miR-21, miR-27b, miR-34a, miR-182, miR-200c and miR-451) were quantified using quantitative real-time PCR (qRT-PCR). The miRNAs expression was categorized into two groups based on upregulation and downregulation. The disease outcome of the patients were evaluated after completion of chemotherapy. Disease-free survival (DFS) analysis using Kaplan-Meier method followed by univariate and multivariate Cox's regression analysis were performed to investigate the impact of these candidate miRNAs on recurrence prediction. Results: The relative expressions of miR-27b and miR-451 were found to be significantly lower in cancerous as compared with normal adjacent tissues of TNBC patients. Multivariate Cox's regression analysis demonstrated that medullary and metaplastic tumor subtypes and positive axillary lymph nodes significantly increased the risk of recurrence in TNBC patients. Downregulated expression of miR-21 and upregulated expression of miR-182 were found to be associated with risk of recurrence in TNBC patients. Conclusion: Tumor subtypes, positive axillary lymph nodes as well as expression profiles of miR-21 and miR-182 could be useful as predictive biomarkers of recurrence in TNBC patients.

A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR-574-5p-ZEB1 axis in triple negative breast cancer.

Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.

Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer.

BackgroundEribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker.MethodsTILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively.ResultsOf the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063).ConclusionThe results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.

O2-7-3 - Prediction of the treatment response to eribulin chemotherapy in breast cancer using tumor-infiltrating lymphocytes

Background: Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker.Methods: TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively.Results: Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063).Conclusion: The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC. Background: Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker. Methods: TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively. Results: Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063). Conclusion: The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.

Abstract 1412: Prediction of the treatment response to eribulin chemotherapy in breast cancer using tumor-infiltrating lymphocytes (TILs)

Abstract Background: Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker. Materials and Methods: TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively. TILs were defined as the infiltrating lymphocytes within tumor stroma and were expressed in proportion to the field investigated. The area of in situ carcinoma and crush artifacts were not included. Proportional scores were defined as 3, 2, 1, and 0 if the area of stroma with lymphoplasmacytic infiltration around invasive tumor cell nests was &amp;gt; 50%, &amp;gt; 10 - 50%, ≤ 10%, and absent, respectively. TILs were considered positive when scores were ≥ 2, and negative when scores were 1 and 0. Results: Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a univariate analysis of recurrence in TNBC patients, being in the high TILs group was a factor for a good outcome (p = 0.047, HR = 0.260). In a multivariate analysis, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063). Conclusions: The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC. Citation Format: Kashiwagi Shinichiro, Yuka Asano, Wataru Goto, Kento Kurata, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Naoyoshi Onoda, Sayaka Tanaka, Masahiko Ohsawa, Masaichi Ohira, Kosei Hirakawa. Prediction of the treatment response to eribulin chemotherapy in breast cancer using tumor-infiltrating lymphocytes (TILs). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1412.

The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients.

The value of adjuvant radiotherapy in triple negative breast cancer (TNBC) remains unclear. A systematic review and meta-analysis was conducted in TNBC patients to assess survival and recurrence outcomes associated with radiotherapy following either breast conserving therapy (BCT) or post-mastectomy radiotherapy (PMRT). Four electronic databases were searched from January 2000 to November 2015 (PubMed, MEDLINE, EMBASE and Web of Science). Studies investigating overall survival and/or recurrence in TNBC patients according to radiotherapy administration were included. A random effects meta-analysis was conducted using mastectomy only patients as the reference. Twelve studies were included. The pooled hazard ratio (HR) for locoregional recurrence comparing BCT and PMRT to mastectomy only was 0.61 (95% confidence interval [CI] 0.41-0.90) and 0.62 (95% CI 0.44-0.86), respectively. Adjuvant radiotherapy was not significantly associated with distant recurrence. The pooled HR for overall survival comparing BCT and PMRT to mastectomy only was 0.57 (95% CI 0.36-0.88) and HR 1.12 (95% CI 0.75, 1.69). Comparing PMRT to mastectomy only, tests for interaction were not significant for stage (p=0.98) or age at diagnosis (p=0.85). However, overall survival was improved in patients with late-stage disease (T3-4, N2-3) pooled HR 0.53 (95% CI 0.32-0.86), and women <40years, pooled HR 0.30 (95% CI 0.11-0.82). Adjuvant radiotherapy was associated with a significantly lower risk of locoregional recurrence in TNBC patients, irrespective of the type of surgery. While radiotherapy was not consistently associated with an overall survival gain, benefits may be obtained in women with late-stage disease and younger patients.

Breast parenchymal signal enhancement ratio at preoperative magnetic resonance imaging: association with early recurrence in triple-negative breast cancer patients

The signal enhancement ratio (SER) of surrounding non-tumor parenchyma at breast magnetic resonance imaging (MRI) can be helpful in breast cancer patients, but has not been investigated in patients with triple negative breast cancer (TNBC). To investigate the association between background parenchymal SER around the tumor on preoperative dynamic contrast-enhanced MRI with recurrence-free survival in patients with TNBC. Between April 2012 and May 2013, 71 TNBC patients who underwent preoperative MRI were included. SER values were calculated from regions of interest placed in the breast parenchyma around the tumor. Cox proportional hazards models were used to determine associations between MRI variables, clinical-pathologic variables, and recurrence-free survival. Recurrence occurred in 8.5% (6/71) of patients. At univariate analysis, a higher SER around the tumor, larger tumor size, lymphovascular invasion, lymph node metastasis, receipt of neoadjuvant chemotherapy, receipt of total mastectomy, and not receiving adjuvant chemotherapy were associated with worse recurrence-free survival. At multivariate analysis of preoperative variables, a higher SER around the tumor was independently associated with worse recurrence-free survival (hazard ratio [HR] = 7.072, P = 0.003 for SER1; HR = 6.268, P = 0.006 for SER2; HR = 3.004, P = 0.039 for SER3). Higher SER around the tumor at preoperative dynamic contrast-enhanced MRI is an independent predictor for recurrence in TNBC patients.

Abstract P6-07-36: A Prognostic Model For Triple-Negative Breast Cancer Patients Based On Node Status, Cathpesin-D And Ki-67

Abstract Background: Triple-negative breast cancer (TNBC) had been classified as a breast cancer subgroup that is negative for ER, PR and HER2. The purpose of this study was to identify prognostic factors affecting outcome in women with TNBC and to construct a prognostic model which can predict recurrence. Material and methods: We retrospectively analyzed the clinicopathologic characteristics and outcome of 284 patients diagnosed with a stage I to III triple negative breast cancer in Shanghai Cancer Hospital, including age, menopausal status, tumor size, node status, grade, ER, PR, HER-2, Cathpesin-D, PS2, Nm23, P53, Bax, Bcl-2, P27, Topo-IIa, GSTn, MDR, Cyclin D1 and Ki67. 196 patients in 2000, 2001 and 2002 belonged to training set. Prognostic significance of factors was assessed using univariate and multivariate analyses, which were combined to build a model. DFS and OS were estimated by the Kaplan-Meier method and compared among groups via the log-rank test. The prognostic value of the model was further validated in separate testing set containing 88 patients in 2003 and 2004. The median age of patients was 50 years (range, 23–85 years). 95.1% patients received cytotoxic chemotherapy after surgery; 216 (76.1%) with anthracycline based, 54 (19.0%) with CMF regimen. Results: The median follow-up duration was 70.6 months, 102 patients (35.9%) experienced recurrence or metastasis. In Cox regression, ≥4 lymph node metastasis (HR = 3.7, P &amp;lt; 0.001), Cath-D positive (HR = 2.1, p = 0.034), and Ki-67 index≥20%, (HR = 2.0, p = 0.006) were identified as independent factors for DFS, only ≥4 lymph node metastasis (HR = 4.9, P &amp;lt; 0.001) showed prognostic significance for OS. The prognostic model is based on the sum total of factors, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. According to the prognostic score, patients were assigned to low-risk group(0 and 1 point) and high-risk group(2 and 3 point). The 5-year DFS rates in two groups were 82.3% and 47.8%, respectively (p &amp;lt; 0.001). The model provided a high predictive accuracy of recurrence, which showed an AUC of 0.71 in the training set and an AUC of 0.70 in validation set. Conclusion: Based on nodal status, Ki-67 and Cathpesin-D, we built a model that had considerable clinical value in predicting recurrence in TNBC patients, which help clinicians guide the appropriate level of adjuvant treatment and scheduling of surveillance visits. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-36.