Research Articles Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)–targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC. Here, we report that MYCN, an oncogene typically overexpressed in tumors of the nervous system or with neuroendocrine features, is heterogeneously expressed within a substantial fraction of primary and recurrent TNBC and is expressed in an even higher fraction of TNBCs that do not display a pathological complete response after neoadjuvant chemotherapy. We performed high-throughput chemical screens on TNBC cell lines with varying amounts of MYCN expression and determined that cells with higher expression of MYCN were more sensitive to bromodomain and extraterminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell lines and patient-derived xenograft (PDX) models. Our preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced MYCN-expressing TNBC.
CONCLUSIONS: LPBC was marginally associated with higher pCR rate than non-LPBC in LT treated HER2+ BC patients. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response. PMID: 31653641 [PubMed - as supplied by publisher]
AbstractBackgroundHER2 blockade in combination with chemotherapy (CT) remains the treatment of choice for patients with early HER2+ BC, irrespective of ER status. Patients with HER2+ early BC co-expressing ER may benefit from HER2 blockade in combination with endocrine therapy (ET) and new targeted agents. Elderly patients benefit from HER2 blockade as much as younger ones but they have higher risks of adverse events, mostly induced by the CT partner, making de-escalation of CT appealing. Recent data have elucidated cyclin-dependent kinases 4 and 6 (CDK4/6) as key therapeutic targets functioning downstream of both ER and H...
Tomás Pascual1,2, Miguel Martin3,4,5, Aranzazu Fernández-Martínez6, Laia Paré1,2, Emilio Alba4,5,7, Álvaro Rodríguez-Lescure4,8, Giuseppe Perrone9, Javier Cortés10,11, Serafín Morales12, Ana Lluch4,5,13,14,15, Ander Urruticoechea16, Blanca González-Farré2,17, Patricia Galván1, Pedro Jares17, Adela Rodriguez1, Nuria Chic1, Daniela Righi9, Juan Miguel Cejalvo1, Giuseppe Tonini9, Barbara Adamo1, Maria Vidal1, Patricia Villagrasa2, Montserrat Muñoz1 and Aleix Prat1,2* 1Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona,...
Conclusion: The administration of trastuzumab should be considered standard treatment for HER2-positive patients who have achieved pCR after NACT alone.Breast Care
Condition: Breast Cancer Interventions: Biological: Pembrolizumab (K); Drug: Placebo (P); Drug: Paclitaxel (X); Drug: Doxorubicin hydrochloride (A); Drug: Epirubicin (E); Drug: Cyclophosphamide (C); Drug: Endocrine therapy; Radiation: Radiation therapy; Procedure: Surgery Sponsor: Merck Sharp & Dohme Corp. Not yet recruiting