scholarly journals Precision medicine in refractory metastatic triple-negative breast cancer is enhanced by molecular subtyping and genomic profiling.

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Breast Cancer ◽  
Confidence Interval ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Therapeutic Benefit ◽  
Percent Confidence Interval ◽  
Molecular Subtyping ◽  
Phase Ib

Triple-negative breast cancer (TNBC) is a very variable disease, and molecular subtyping may enable more precise diagnosis and treatment. Our earlier work categorized TNBCs into four subgroups, each with its own set of potential treatment targets. To assess the effectiveness of these targets, we performed the study, a phase Ib/II subtyping-based and genomic biomarker-guided umbrella study. Patients with refractory metastatic TNBC were enrolled and assigned to one of seven arms: (A) pyrotinib plus capecitabine, (B) androgen receptor inhibitor plus CDK4/6 inhibitor, (C) anti-PD-1 plus nab-paclitaxel, (D) PARP inhibitor plus nab-paclitaxel, (E) and (F) anti-VEGFR plus nab-paclitaxel, or (G The major outcome measure was the rate of objective response (ORR). We included 69 patients with resistant metastatic TNBC who had previously received a median of three lines of treatment (range, 1-8). Twenty-nine (29.0 percent, 95 percent confidence interval (CI): 18.7 percent -41.2 percent ) of the 69 intention-to-treat (ITT) patients obtained an objective response. Our findings indicated that immunotherapy (arm C) had the greatest ORR (52.6 percent, 95 percent confidence interval [CI]: 28.9 percent -75.6 percent ) in the ITT group. Arm E had a good ORR (26.1 percent, 95 percent CI: 10.2 percent -48.4 percent in the ITT group), but was associated with a higher prevalence of severe adverse events (grade 3). Somatic mutations in TOP2A and CD8 immunohistochemistry score may be able to predict immunotherapy response in patients with TNBC classified as immunomodulatory. In conclusion, the phase Ib/II study demonstrated the therapeutic benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

Precision medicine in refractory metastatic triple-negative breast cancer is enhanced by molecular subtyping and genomic profiling

2021 ◽  
Author(s):  
Oliwier Morin ◽  
Brandon Weston ◽  
Taylan Burke ◽  
George Brock ◽  
James D. Klingensmith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Outcome Measure ◽  
Parp Inhibitor ◽  
Therapeutic Benefit ◽  
Molecular Subtyping ◽  
Intention To Treat ◽  
Grade 3

Triple-negative breast cancer (TNBC) is a very variable disease, and molecular subtyping may enable moreprecise diagnosis and treatment. Our earlier work categorized TNBCs into four subgroups, each with its ownset of potential treatment targets. To assess the effectiveness of these targets, we performed the study, a phaseIb/II subtyping-based and genomic biomarker-guided umbrella study. Patients with refractory metastaticTNBC were enrolled and assigned to one of seven arms: (A) pyrotinib plus capecitabine, (B) androgenreceptor inhibitor plus CDK4/6 inhibitor, (C) anti-PD-1 plus nab-paclitaxel, (D) PARP inhibitor plus nabpaclitaxel,(E) and (F) anti-VEGFR plus nab-paclitaxel, or (G The major outcome measure was the rate ofobjective response (ORR). We included 69 patients with resistant metastatic TNBC who had previouslyreceived a median of three lines of treatment (range, 1-8). Twenty-nine (29.0 percent, 95 percent confidenceinterval (CI): 18.7 percent -41.2 percent ) of the 69 intention-to-treat (ITT) patients obtained an objectiveresponse. Our findings indicated that immunotherapy (arm C) had the greatest ORR (52.6 percent, 95 percentconfidence interval [CI]: 28.9 percent -75.6 percent ) in the ITT group. Arm E had a good ORR (26.1 percent,95 percent CI: 10.2 percent -48.4 percent in the ITT group), but was associated with a higher prevalence ofsevere adverse events (grade 3). Somatic mutations in TOP2A and CD8 immunohistochemistry score may beable to predict immunotherapy response in patients with TNBC classified as immunomodulatory. Inconclusion, the phase Ib/II study demonstrated the therapeutic benefit of subtyping-based targeted therapy forrefractory metastatic TNBC.

The Impact of Platinum-Containing Chemotherapies in Advanced Triple-Negative Breast Cancer: Meta-Analytical Approach to Evaluating Its Efficacy and Safety

2021 ◽  
pp. 1-10
Author(s):  
Rui Yang ◽  
You-Yang Shi ◽  
Xiang-Hui Han ◽  
Sheng Liu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Cochrane Library ◽  
Control Group ◽  
Chemotherapy Group ◽  
Significant Difference ◽  
The Impact

<b><i>Background:</i></b> Triple-negative breast cancer (TNBC), the most common type of breast cancer, is associated with poor patient prognosis. Platinum-containing chemotherapies are commonly used in the treatment and prevention of advanced TNBC. <b><i>Objectives and Methods:</i></b> To systematically evaluate the effectiveness and safety of platinum-containing chemotherapies in patients with advanced TNBC, we searched several databases, including PubMed, Medline, Embase, ClinicalTrials.gov, Cochrane Library, CNKI, CBM, and the Chinese Cochrane Center, to collect published randomized controlled clinical studies of platinum-containing chemotherapies for advanced TNBC before November 2020. The meta-analysis was performed using Review Manager version 5.3. To assess effectiveness and safety, dichotomous and continuous variables were assessed using odds ratio (OR) and mean difference (MD), respectively, with 95% CI. <b><i>Results:</i></b> A total of 1,222 patients with advanced TNBC were enrolled in 11 eligible trials, including 489 patients in the treatment group (platinum-containing) and 447 patients in the control group (non-platinum-containing). We also retrieved information whether a PARP inhibitor was combined with platinum-containing chemotherapy for patients with metastatic TNBC and identified 224 patients who received a PARP inhibitor combined with platinum-containing chemotherapy and 62 patients in the platinum-containing group who did not. The platinum-containing chemotherapy group had a significantly better objective response rate (OR 1.43, 95% CI 1.20–1.71, <i>p</i> &#x3c; 0.001) and longer progression-free survival (PFS; MD 1.15, 95% CI 0.03–2.28, <i>p</i> &#x3c; 0.05) than the non-platinum-containing chemotherapy group. However, there was no significant difference in overall survival (OS) of patients with advanced TNBC between the two groups (MD 2.04, 95% CI –0.83 to 4.91, <i>p</i> &#x3e; 0.05). Related adverse effects of platinum-containing chemotherapies involved gastrointestinal reaction, myelosuppression and liver function damage. Platinum-containing chemotherapies were not associated with an increased incidence of adverse side effects compared with non-platinum-containing chemotherapies, with the exception of nausea and vomiting (OR 2.22, 95% CI 1.10–4.46, <i>p</i> &#x3c; 0.05). Furthermore, the addition of the PARP inhibitor iniparib to gemcitabine and carboplatin treatment improved the rate of clinical benefit, OS and PFS. <b><i>Conclusions:</i></b> Platinum-containing chemotherapy remains a highly recommended therapeutic regimen due to greater effectiveness and tolerance for patients with advanced TNBC.

scholarly journals Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 2056
Author(s):  
Kitti Andreidesz ◽  
Balazs Koszegi ◽  
Dominika Kovacs ◽  
Viola Bagone Vantus ◽  
Ferenc Gallyas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Combined Treatment ◽  
Parp Inhibition ◽  
Akt Pathway ◽  
Platinum Compound ◽  
Mcf7 Cells ◽  
Cancer Line

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.

scholarly journals Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor

2021 ◽  
Author(s):  
Dandan Song ◽  
Huan He ◽  
Indranil Sinha ◽  
Linnea Hases ◽  
Feifei Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor

Abstract 1066: Pre-clinical combination of a PARP inhibitor, talazoparib, and carboplatin in triple-negative breast cancer

2021 ◽  
Author(s):  
Alexia Cotte ◽  
Michèle Beniey ◽  
Takrima Haque ◽  
Nelly Béchir ◽  
Audrey Hubert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor

A phase Ib study of TQB2450 plus anlotinib in patients with advanced triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1074-1074
Author(s):  
Jiayu Wang ◽  
Binghe Xu ◽  
Tao Sun ◽  
Quchang Ouyang ◽  
Yiqun Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Dose Escalation ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Expansion Phase ◽  
Qt Interval Prolongation ◽  
Grade 3

1074 Background: TQB2450 is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). Anlotinib is an antiangiogenic small molecule, multi-target tyrosine kinase inhibitor that has improved clinical outcomes in various solid tumors. This phase 1b study aims to evaluate the safety and efficacy of TQB2450 plus anlotinib for patients with advanced triple-negative breast cancer (TNBC) after the failure of standard therapy. Methods: This ongoing study included a dose-escalation phase and an expansion phase. Advanced TNBC patients with prior anthracyclines and/or taxanes treatment and failed at least first-line therapy were enrolled. In the dose-escalation phase, eligible patients received anlotinib (8mg, 10mg, and 12mg, qd, days 1-14; 21 days per cycle) plus TQB2450 (1200mg, day 1; 21 days per cycle) following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase, eligible patients were enrolled into the expansion cohort. The primary endpoint was objective response rate (ORR), and the secondary endpoints were overall survival (OS), disease control rate (DCR), progression-free survival (PFS), and safety. Results: Between May 29, 2019, and December 31, 2020, in the dose-escalation phase, three patients receiving 10mg anlotinib plus 1200mg TQB2450 had no DLTs in the first cycle, neither did three patients with 12mg anlotinib plus TQB2450. Next, 28 patients with advanced TNBC received 12 mg anlotinib plus TQB2450 in the expansion phase. Finally, a total of 34 patients were included with median age of 49.5 (32-70) and median prior lines of 2 (1-6). Numbers of patients with prior platinum therapy: 16, prior anthracycline therapy: 32. The ORR was 26.47% (9/34) and DCR was 82.35% (28/34). The median PFS was 8.57 months. Seventeen patients experienced grade 3 treatment-related AEs (TRAEs). Most frequently occurring (>5%) grade 3 TRAEs were QT interval prolongation (17.65%), hypertension (14.71%), diarrhea (8.82%), hand-foot syndrome (HFS) (8.82%), and hypertriglyceridemia (5.88%). Conclusions: TQB2450 plus anlotinib showed an acceptable safety profile with promising activity for previously anthracyclines and/or taxanes-treated advanced TNBC patients. Clinical trial information: NCT03855358 .[Table: see text]

scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

scholarly journals Synergistic Interaction Betweem Olaparib, a Parp Inhibitor, and Cytotoxic Agent in Triple Negative Breast Cancer

2013 ◽  
Vol 24 ◽  
pp. ix59 ◽  
Author(s):  
J. Hashimoto ◽  
Y. Kitamura ◽  
Y. Takashima ◽  
Y. Kodera ◽  
S. Shimma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Synergistic Interaction ◽  
Cytotoxic Agent
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