PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS591-TPS591 ◽  
Author(s):  
Helena Margaret Earl ◽  
Anne-Laure Vallier ◽  
Wendi Qian ◽  
Louise Grybowicz ◽  
Stanly Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Triple Negative ◽  
Alternative Hypothesis ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Open Label ◽  
Significance Level ◽  
Platinum Based Chemotherapy ◽  
Stage 1

TPS591 Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].

scholarly journals Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 259
Author(s):  
Madhuchhanda Kundu ◽  
Sumita Raha ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Healthy Controls ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Patient Derived Xenograft

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

scholarly journals Tribbles Homolog 3 Involved in Radiation Response of Triple Negative Breast Cancer Cells by Regulating Notch1 Activation

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 127 ◽  
Author(s):  
Yueh-Chun Lee ◽  
Wen-Ling Wang ◽  
Wei-Chao Chang ◽  
Yu-Hao Huang ◽  
Guan-Ci Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Cancer Patients ◽  
Triple Negative ◽  
Mass Spectrometry Analysis ◽  
Radiation Response ◽  
Stem Cell Population ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Poor Prognostic Factor

Breast cancer is the most common cancer for women in Taiwan and post-lumpectomy radiotherapy is one of the therapeutic strategies for this malignancy. Although the 10-year overall survival of breast cancer patients is greatly improved by radiotherapy, the locoregional recurrence is around 10% and triple negative breast cancers (TNBCs) are at a high risk for relapse. The aim of this paper is to understand the mechanisms of radioresistance in breast cancers which may facilitate the development of new treatments in sensitizing breast cancer toward radiation therapy. Tribbles homolog 3 (TRIB3) is a pseudokinase protein and known to function as a protein scaffold within cells. It has been reported that higher TRIB3 expression is a poor prognostic factor in breast cancer patients with radiotherapy. In this study, we investigate the involvement of TRIB3 in the radiation response of TNBC cells. We first found that the expression of TRIB3 and the activation of Notch1, as well as Notch1 target genes, increased in two radioresistant TNBC cells. Knockdown of TRIB3 in radioresistant MDA-MB-231 TNBC cells decreased Notch1 activation, as well as the CD24-CD44+ cancer stem cell population, and sensitized cells toward radiation treatment. The inhibitory effects of TRIB3 knockdown in self-renewal or radioresistance could be reversed by forced expression of the Notch intracellular domain. We also observed an inhibition in cell growth and accumulated cells in the G0/G1 phase in radioresistant MDA-MB-231 cells after knockdown of TRIB3. With immunoprecipitation and mass spectrometry analysis, we found that, BCL2-associated transcription factor 1 (BCLAF1), BCL2 interacting protein 1 (BNIP1), or DEAD-box helicase 5 (DDX5) were the possible TRIB3 interacting proteins and immunoprecipitation data also confirmed that these proteins interacted with TRIB3 in radioresistant MDA-MB-231 cells. In conclusion, the expression of TRIB3 in radioresistant TNBC cells participated in Notch1 activation and targeted TRIB3 expression may be a strategy to sensitize TNBC cells toward radiation therapy.

Clinicopathologic characteristics of triple-negative breast cancer and relationship to basal markers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11519-e11519
Author(s):  
Dimitrios Tryfonopoulos ◽  
Georgios Oikonomopoulos ◽  
Stamatina Demiri ◽  
Lazaros Lekakis ◽  
Nikolaos Fragkiskos Pistamaltzian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Stage Iv ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Clinicopathologic Characteristics ◽  
Ki 67 ◽  
Immunohistochemical Markers ◽  
Gene Expression Studies

e11519 Background: Triple negative breast cancers are immunohistochemical surrogates of basal-like breast cancers. There is no complete overlap between triple negative and basal-like tumors and as gene expression studies evolve, further subclassification bearing clinical relevance is underway. Our purpose was to correlate clinicopathologic characteristics of triple negative breast cancer tumors with expression of basal markers in an effort to define immunohistochemically subgroups of this heterogenous disease Methods: Data were retrieved and analysed using our electronic databank. Patient samples were reviewed by an expert breast cancer pathologist and stained additionally for EGFR and CK 5/6 antibodies. Results: Sixty-five women with triple negative breast cancer were identified. Mean age was 58.3±12.9 years. Most tumors (86%) were of ductal histology, 53% grade 3, 48% having high Ki-67 index (>14%). 10% of patients presented with Stage IV, 25% with Stage III, 38% with stage II and 27% with stage I disease. 63% of patients were postmenopausal. EGFR staining was present in 43% of tumor samples, whereas CK 5/6 in 38.5%. Both EGFR and CK 5/6 expression was found in 18.5%, whereas 37% of tumors expressed neither EGFR or CK 5/6. No difference was observed between tumors expressing any of these 2 basal markers as compared to EGFR and CK 5/6 negative tumors in terms of Ki-67 index, grade, tumor size and nodal involvement. Lymphovascular invasion and non-ductal histology tended to occur more frequently (p=ns) in non-basal tumors. Additionally, patients with expression of any of the basal markers tended to be more obese than the non-basal triple negative breast cancer patients (p=ns). Conclusions: Further immunohistochemical markers apart from EGFR and CK 5/6 are needed in order to further define clinically meaningful subgroups of triple negative breast cancer.

Biopsy-driven study to identify biomarkers of drug resistance in patients with triple-negative breast cancer.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 87-87
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Elaheh Ahmadzadeh ◽  
Ewa Przybytkowski ◽  
Carole Seguin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Great Difficulty ◽  
Clinical Samples ◽  
Drug Resistant ◽  
Breast Cancers ◽  
Breast Cancer Patients

87 Background: Resistance to chemotherapy is the underlying cause of death in most patients dying of breast cancer. Patients with early stages of breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis, while women with advanced breast cancer live as long as their tumors respond to chemotherapy. Because of the great difficulty of obtaining clinical samples from drug resistant tumors in patients, there is scant information about molecular factors from actual drug resistant tumors. This project aims to systematically profile resistant triple negative breast cancers (TNBCs) in order to discover molecular “resistance” genes/proteins as a first step to develop strategies to overcome drug resistance. Methods: Paired biopsies are collected from TNBC patients (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Results: We have currently enrolled 28 patients in the neoadjuvant setting and 3 metastatic patients. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. In parallel, we have generated acquired resistance to paclitaxel in a panel of TNBC cell lines. These cell lines will also undergo genomic profiling and exome sequencing to identify molecular markers of resistance that will be correlated with the markers found in patient samples. Conclusions: This project will allow us to identify the molecular factors responsible for drug resistance in TNBCs and enable the elaboration of strategies to overcome resistance.

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