scholarly journals The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5091
Author(s):  
Héctor Martínez-Gregorio ◽  
Ernesto Rojas-Jiménez ◽  
Javier César Mejía-Gómez ◽  
Clara Díaz-Velásquez ◽  
Rosalía Quezada-Urban ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Nodes ◽  
Triple Negative Breast Cancer ◽  
Genetic Heterogeneity ◽  
Triple Negative ◽  
Early Stage ◽  
Genetic Alterations ◽  
Evolutionary Development ◽  
Tumor Evolution ◽  
Skin Metastases

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.

Optimizing Chemotherapy in Triple-Negative Breast Cancer: The Role of Platinum

2014 ◽  
pp. e37-e42 ◽  
Author(s):  
Melinda Telli
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Randomized Clinical Trials ◽  
Triple Negative ◽  
Early Stage ◽  
Breast Cancer Subtype ◽  
Brca2 Mutation ◽  
Genetic Alterations ◽  
Brca1 And Brca2 ◽  
Repair Capacity

Although characterization of triple-negative breast cancer (TNBC) using mRNA gene expression profiling has certainly provided important insights, the concept of targeting DNA repair defects with DNA damaging therapeutics such as platinum in TNBC has been advanced from studies focusing on both germline and somatic genetic alterations associated with this breast cancer subtype. A growing body of preclinical and clinical data suggests that platinum chemotherapy has a potential role to play in the treatment of both early-stage and advanced TNBC, though results are not yet definitive. Randomized clinical trials that incorporate biomarkers of response, including germline BRCA1 and BRCA2 mutation status as well as tumor-based measures of genomic “scarring” resulting from the accumulation of DNA damage in tumors with deficient repair capacity, will help to clarify the optimal use and activity of platinum in TNBC.

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 Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

PD-L1 expression and TOP3A mutation as prognostic factors for adjuvant chemotherapy in triple negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 541-541
Author(s):  
Xue Wang ◽  
Peng Yuan ◽  
Feng Du ◽  
Lina Cui ◽  
Fangchao Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Functional Enrichment ◽  
Pathway Enrichment Analysis ◽  
Genetic Characteristics ◽  
Significant Difference

541 Background: Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is markedly heterogeneous and lacks specific targets. The aim of this study is to explore potential predictors and therapeutic targets based on clinical and genetic characteristics. Methods: 138 patients with triple-negative breast cancer after surgical treatment were 1:1 randomly assigned to the paclitaxel combined with carboplatin (TCb) group or the epirubicin combined with cyclophosphamide sequential paclitaxel (EC-T) adjuvant chemotherapy group. PD-L1 was retrospectively analyzed by surgically resected specimens, and 733 cancer-related genes were detected by NGS. Pathway enrichment analysis was performed using DAVID for functional enrichment genetic alterations. Cox regression models and Kaplan-Meier were used to evaluate disease-free survival (DFS). Results: In this study, there was no significant difference in DFS between the TCb and EC-T groups. 31 (22.5%) of 138 TNBC patients were positive for PD-L1 expression, including 15 (10.9%) patients positive for PD-L1 in tumor cells (TCs) and 29 (21.0%) patients positive for PD-L1 in tumor-infiltrating immune cells (TICs). Patients with positive PD-L1 expression, either in TCs or TICs, achieved better DFS [HR=0.13 (95% CI: 0.02-0.93), p=0.016], the difference was also shown in the EC-T group [HR=0 (95% CI: 0- inf), p=0.037], but not in the TCb group [HR=0 (95% CI: 0.04-2.1), p=0.189]. In addition, we identified 7 patients with mutations in DNA topoisomerase IIIα(TOP3A), a homologous recombination (HR)-related gene, and patients with mutations in this gene had worse DFS than those without mutations [HR=4]. However, there was no statistically significant association between BRCA mutation and response to either therapeutic regimens. Conclusions: In this TNBC patient population, immunohistochemistry (IHC) and NGS analyses identified potential prognostic markers. PD-L1 positive and TOP3A mutation were significantly associated with early triple-negative breast cancer prognosis.

scholarly journals Practical Approach to Triple-Negative Breast Cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 293-300 ◽  
Author(s):  
Vijayakrishna K. Gadi ◽  
Nancy E. Davidson
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Early Stage ◽  
Management Strategies ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Epidermal Growth ◽  
Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

Early triple-negative breast cancer in women aged ≥65: retrospective study of outcomes, resource use and costs, 2010–2016

2020 ◽  
Author(s):  
Jan Sieluk ◽  
Amin Haiderali ◽  
Min Huang ◽  
Lingfeng Yang ◽  
Kim M Hirshfield
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Resource Use ◽  
Median Overall Survival ◽  
Triple Negative ◽  
Healthcare Resource ◽  
Early Stage ◽  
Stage Ii ◽  
Medicare Database ◽  
Therapy Treatment

Aim: To examine real-world treatment patterns and outcomes in neoadjuvant and adjuvant settings for early-stage triple-negative breast cancer (TNBC). Patients & methods: Using the SEER-Medicare database, we identified patients (≥65 years) with newly diagnosed stage II/III TNBC in 2010–2015 who had surgery plus neoadjuvant and/or adjuvant (systemic and/or radiation) therapy. Treatment, survival, healthcare resource use and costs were assessed through 2016. Results: Of 1569 patients (>99% women), 6%/74%/20% received neoadjuvant-only/adjuvant-only/both (neo + adj) therapies, respectively. Median overall survival was 23 months/not reached (NR)/78 months, with longer survival at stage II (NR/NR/78 months) than stage III (22/43/38 months). Mean per-patient-per-month costs were $10,620 and $17,872 in neoadjuvant and adjuvant periods. Conclusion: These findings provide insights into clinical and economic outcomes for early-stage TNBC in 2010–2016.

Sign in / Sign up

Export Citation Format

Share Document