scholarly journals Transcriptome Analysis Derives a Novel Prognostic 7-mRNA Signature in Early-Stage Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Yun-Song Yang ◽  
Yi-Xing Ren ◽  
Shuang Hao ◽  
Xiao-En Xu ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Prognostic Value ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Distant Recurrence ◽  
Cancer Center ◽  
Transcriptome Data ◽  
Normal Tissues

Abstract Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and patients with early-stage TNBCs have distinct likelihood of distant recurrence. Methods: In this study, We extracted transcriptome data for 189 pathologically confirmed pT1-2 node-negative TNBC patients at Fudan University Shanghai Cancer Center. Candidate mRNAs were filtered, which was followed by differential expressed mRNAs analysis, survival analysis, and LASSO Cox regression model. All-subsets regression program was used for constructing a multi-mRNA signature in the training set (n=159); the accuracy and prognostic value were then validated using an independent validation set (n=158). Results: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues, and developed a prognostic signature based on seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2).In both the training (n=159) and validation cohorts (n=158), the signature could identify patients with relatively high recurrence risks and serve as an independent prognostic factor. Furthermore, the signature had better prognostic value than traditional clinicopathological features in both sets. Among the seven mRNAs, TMEM101 was identified as a prognostic biomarker of early-stage TNBC. Additional cell experiments suggested that TMEM101 could facilitate migration and proliferation of TNBC cells. Conclusions: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. Clinical and genomic low risk TNBC patients may safely avoid adjuvant chemotherapy.

scholarly journals The Early-Stage Triple-Negative Breast Cancer Landscape Derives a Novel Prognostic Signature and Therapeutic Target

2021 ◽  
Author(s):  
Yun-Song Yang ◽  
Yi-Xing Ren ◽  
Cheng-Lin Liu ◽  
Shuang Hao ◽  
Xiao-En Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Prognostic Value ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Cancer Center ◽  
Transcriptome Data ◽  
Prognostic Signature

Abstract Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. Current therapeutic guidance is still limited.Methods: We extracted transcriptome data for 189 pathologically confirmed pT1-2N0M0 TNBC patients at Fudan University Shanghai Cancer Center. Candidate mRNAs were filtered, which was followed by differential expressed mRNAs analysis, survival analysis, and LASSO Cox regression model. All-subsets regression program was used for constructing a multi-mRNA signature in the training set (n=159); the accuracy and prognostic value were then validated using an independent validation set (n=158). Results: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs are featured of basal-like and immune-suppressed subtype and homologous recombination ability deficiency. We developed a prognostic signature contained seven mRNAs from transcriptome data (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n=159) and validation cohorts (n=158), the signature could identify patients with relatively high recurrence risks and serve as an independent prognostic factor. The signature had better prognostic value than traditional clinicopathological features in both sets. Among the seven mRNAs, TMEM101 is highly expressed in TNBC and represents a potential therapeutic target. Inhibition of TMEM101 impaired tumor progression.Conclusions: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. Clinical and genomic low risk TNBC patients may have the opportunity to avoid adjuvant chemotherapy

321 Phase I clinical trial assessing the combination of systemic chemokine modulatory regimen targeting TLR3 with neoadjuvant chemotherapy in triple negative breast cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A347-A347
Author(s):  
Shipra Gandhi ◽  
Mateusz Opyrchal ◽  
Cayla Ford ◽  
Victoria Fitzpatrick ◽  
Melissa Grimm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Standard Dose ◽  
Surrogate Marker ◽  
Comprehensive Cancer Center ◽  
Cancer Center

BackgroundNeoadjuvant chemotherapy (NAC) with taxanes is the standard of care in triple negative breast cancer (TNBC). Intratumoral prevalence of CD8+ cytotoxic T-lymphocytes (CTLs) is associated with an improvement in relapse-free survival (RFS) and overall survival (OS), while regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) are associated with poor survival. Higher ratio of CTL/Treg is associated with higher probability of obtaining pathological complete response (pCR), a surrogate marker for RFS. Intratumoral production of CCL5, CXCL9, CXCL10 and CXCL11 is critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction. Previous studies have shown that CXCL9 expression in the pre-treatment breast tissue is associated with a three-fold higher rate of achieving pCR. Our preclinical data show that Chemokine modulating (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b, and celecoxib (COX-2 inhibitor) increases CTL-attracting, and decreases MDSC-, Treg-favoring chemokines, increasing CTL/Treg ratio in tumor microenvironment, with preferential tumor tissue activation than adjacent healthy tissues. We hypothesize that the combination of CKM with paclitaxel will result in infiltration of TNBC with CTLs, and along with doxorubicin/cyclophosphamide (AC), result in higher pCR, translating into improved RFS and OS.MethodsIn this phase I study NCT04081389, eligibility includes age ≥18 years, confirmed resectable TNBC, radiographically measurable disease ≥1 cm, ECOG PS ≤ 2, adequate organ and marrow function. Patients with autoimmune disease, serious mood disorders, invasive carcinoma within 3 years, history of peptic ulcers or hypersensitivity to NSAIDs will be excluded. We plan to treat three patients with early stage TNBC with paclitaxel 80 mg/m2 IV weekly for 12 weeks, rintatolimod 200 mg IV, celecoxib 200 mg oral twice daily, and accelerated titration of IFN-α2b at doses 0, 5, or 10 million units (MU)/m2 [Dose Levels (DL) 1, 2 and 3 respectively] on days 1–3 (no intra-patient dose escalation) in weeks 1–3. Dose-limiting toxicity (DLT) is defined as grade 3 or higher toxicities within the first 3 weeks. Any DLT will mandate recruitment per the 3+3 model. If no DLT, three patients will be enrolled at DL 4 at 20 MU/m2 IFN- α2b. This will be followed by standard dose-dense AC, and then surgery. The primary endpoint is safety and tolerability of combination and to identify the appropriate DL of CKM and paclitaxel for extended efficacy study. The secondary endpoints include investigation of efficacy (pCR and breast MRI response), along with RFS and OS. Intratumoral biomarkers will be analyzed in an exploratory manner.ResultsN/AConclusionsN/ATrial RegistrationNCT04081389Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-73718.

scholarly journals Breast Cancer: 2021 ASCO Annual Meeting Highlights for the Advanced Practitioner

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Sheeba Cantanelli, MPAS, PA-C
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Parp Inhibitor ◽  
Metastatic Breast ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Vitamin D Levels ◽  
The Impact

Sheeba Cantanelli, MPAS, PA-C, of UT Southwestern Medical Center, Simmons Comprehensive Cancer Center, discusses results from studies evaluating adjuvant therapy with a PARP inhibitor in BRCA-mutated HER2-negative metastatic breast cancer; immunotherapy in the treatment of early-stage triple-negative breast cancer; adjuvant capecitabine after neoadjuvant chemotherapy in triple-negative breast cancer; the addition of palbociclib to fulvestrant in HR-positive, HER2-negative advanced breast cancer; and the impact of vitamin D levels on outcomes. Reporting is provided by The ASCO Post.

Outcomes associated with adjuvant radiation after lumpectomy for elderly women with T1-2N0M0 triple-negative breast cancer: SEER analysis.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 39-39 ◽  
Author(s):  
Sean Szeja ◽  
Sandra S. Hatch
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Elderly Women ◽  
Early Stage ◽  
Estrogen Receptor Status ◽  
Adjuvant Radiation ◽  
Seer Database ◽  
Future Prospective Study

39 Background: Adjuvant Radiation (RT) may be omitted for elderly women with early stage breast cancer having favorable estrogen receptor status, however in the setting of triple negative breast cancer (TNBC), less evidence exists to guide decision making. As some findings thus far have shown TNBC to have an increased recurrence rate, this is an important subject to address. The purpose of this study is to use the Surveillance, Epidemiology, and End Result (SEER) database to evaluate how the addition of adjuvant radiation affects the survival of women ages 70 and above with T1-2, N0, M0 TNBC that undergo Lumpectomy (L). Methods: Cases diagnosed from 2010-2011 were downloaded from the SEER Database. Inclusion criteria were ages 70 and above, with T1-2N0M0 TNBC. Kaplan meier curves calculated overall survival (OS) and disease specific survival (DSS) in months (m). Log-Rank tests were performed to compare survival. Cox multivariate regression was performed to calculate Hazard Ratios (HR) and control for confounding variables including neoadjuvant chemotherapy, number of lymph nodes sampled, age, laterality, grade, T stage, extent of surgery, existence of other cancers. Results: From 2010-2011, SEER contained 109,559 cases of breast cancer with recorded results of Her-2-neu (H2N) status. Combining other receptor values, showed 12,620 triple-negative, which was 12% of cases. Of these, 6980 (55%) had stage T1-2, N0, M0. Lumpectomy was used in 4002 of these cases. There were 974 lumpectomy cases of women aged 70 and above. RT was given in 662 (68%) cases. After 23 months, L+ RT was associated with improved OS at 98.2% compared to 85.6% for L only (p=<0.001), as well as DSS at 99% for L+RT better than 94% for L only (p=0.003). Cox Regression showed radiation demonstrated improved OS (HR=0.14, p<0.001) and DSS (0.14, p=0.01). Conclusions: The use of adjuvant RT after lumpectomy for elderly women with early stage TNBC was associated with improved OS and DSS. Noting the potential for selection bias in this study, future prospective study is required to define the management of early stage triple negative breast cancer.

scholarly journals Real-world treatment patterns and effectiveness outcomes in patients with early-stage triple-negative breast cancer

2021 ◽  
Author(s):  
Amin Haiderali ◽  
Whitney C Rhodes ◽  
Santosh Gautam ◽  
Min Huang ◽  
Jan Sieluk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Real World ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Unmet Need ◽  
Complete Response ◽  
Treatment Patterns ◽  
Neoadjuvant Systemic Therapy

Background: This retrospective, observational study examined real-world treatment patterns and effectiveness outcomes in 450 patients with stage II–IIIB early-stage triple-negative breast cancer treated in the community oncology setting. Methods: Kaplan–Meier methods were used to evaluate event-free survival (EFS), time to recurrence and overall survival (OS). Cox regression models were used to evaluate predictors of EFS and OS by pathological complete response (pCR) status. Results: Among patients receiving neoadjuvant systemic therapy only, pCR was a predictor of EFS and OS. Conclusion: These results highlight the unmet need for therapies that improve outcomes for patients with early-stage triple-negative breast cancer including increasing rates of pCR among patients receiving neoadjuvant therapy.

scholarly journals The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer

2014 ◽  
Vol 3 (1) ◽  
pp. 2 ◽  
Author(s):  
Priyanka Sharma ◽  
Shane R Stecklein ◽  
Bruce F Kimler ◽  
Geetika Sethi ◽  
Brian K Petroff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Triple Negative ◽  
Early Stage ◽  
Brca1 Promoter ◽  
Brca1 Promoter Methylation

scholarly journals Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial

2019 ◽  
Vol 37 (36) ◽  
pp. 3484-3492 ◽  
Author(s):  
Priyanka Sharma ◽  
William E. Barlow ◽  
Andrew K. Godwin ◽  
Eileen E. Parkes ◽  
Laura A. Knight ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes

PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated ( r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

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