Abstract P234: ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer

2021 ◽  
Author(s):  
Melissa R. Junttila ◽  
Jason E. Long ◽  
Robert Warne ◽  
Sunghwan Kim ◽  
Younho Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Preclinical Studies ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Orally Bioavailable ◽  
Positive Breast Cancer

scholarly journals Targeting Cancer Stem Cells and Metastasis with Epigenetic Modulation and Anti-HER2 Therapy: Phase I/II Trial of Vorinostat in Combination with Lapatinib

2020 ◽  
pp. 1-12
Author(s):  
Saranya Chumsri ◽  
Amanda Schech ◽  
Angela Brodie ◽  
Jane Lewis ◽  
Katherine Tkaczuk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Phase I ◽  
Single Agent ◽  
Preclinical Studies ◽  
Her2 Positive ◽  
Mesenchymal Transition ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Purpose: Considerable preclinical and clinical data indicate that only a small subset of tumor cells has longterm proliferating capacity. These cells are termed cancer stem cells (CSCs). Failure to eradicate CSCs is hypothesized to be a cause of cancer recurrence after potentially curative therapies. Therefore, approaches that target CSCs have the potential to improve outcomes. We evaluated the combination of vorinostat and lapatinib to target CSCs and metastasis. Experimental Design: We conducted preclinical studies and a phase I/II clinical trial to determine the effects of vorinostat and lapatinib to CSCs. Results: Our preclinical studies demonstrated that vorinostat and lapatinib further reduced CSCs compared to either single agent. Reduction in self-renewal proteins, mammospheres, epithelial-mesenchymal transition (EMT) markers, and cell migration was also observed. Based on these findings, the combination was evaluated in the phase I trial to which a total of 12 patients were enrolled. Dose-limiting toxicity was not observed in phase I, and the recommended phase II dose was vorinostat 400 mg 4 days on 3 days off and lapatinib 1,250 mg daily. In HER2-positive breast cancer patients, the clinical benefit rate was observed in 43% of subjects. Interestingly, patients who remained on vorinostat and lapatinib did not develop any new site of metastasis. Conclusion: The combination of vorinostat and lapatinib is safe and active in HER2-positive breast cancer. Further studies are needed to evaluate this strategy to target CSCs and metastasis.

scholarly journals Pyrotinib in the treatment of women with advanced HER2 positive breast cancer: A multicenter, prospective, real-world study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13012-e13012
Author(s):  
Jifeng Feng ◽  
Lili Zhang ◽  
Xiaohong Wu ◽  
Jun Zhou ◽  
Mingzhen Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Real World ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy Evaluation ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her2 Breast Cancer ◽  
Positive Breast Cancer

e13012 Background: Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy of pyrotinib in patients with different baseline characteristics in the actual clinical practice has been rarely reported. This study analyzed the efficacy and safety of pyrotinib in the real world. Methods: Patients with histologically confirmed advanced HER2 positive breast cancer were included in the analyses. All patients received pyrotinib-based therapy were given pyrotinib once a day in a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included adverse events (AE), objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: A total of 132 patients (median age: 52 years [29-78]) were enrolled from February 2019 to March 2020. 94(71.21%) patients had visceral metastatic lesions and 20 (15.15%) had brain metastases. HR+, HR-, or unknown HR status for primary tumor accounted for 56.82%, 42.42%, 0.76%, respectively. 115(87.12%) patients were previously administered with trastuzumab. 96(72.73%) patients received pyrotinib-based therapy as a second or further line of treatment. 94(71.21%) patients initiated pyrotinib treatment at 400 mg. Treatment regimens were pyrotinib plus capecitabine (55.30%), pyrotinib combined with trastuzumab (18.18%), and pyrotinib monotherapy (8.33%), pyrotinib combined with endocrine therapy, radiotherapy or antiangiogenic drugs (3.79%). A total of 132 patients were included in PFS analysis. mPFS was 12.0 months (95%CI 8.1-18.8). mPFS for patients without primary trastuzumab-resistant breast cancer was 14.1 months (95%CI 8.7-23.3). Patients receiving pyrotinib-based therapy as their ≥3 lines treatment had lower mPFS than those receiving pyrotinib-based therapy as their < 3 lines treatment (8.8 vs. 15.1 months, P= 0.119). mPFS in patients receiving regimen with and without capecitabine were 15.1 months and 8.4 months, respectively ( P= 0.081). As of data cutoff, mOS has not yet been reached. Among the 65 patients available for efficacy evaluation, 1 (1.54%) patient achieved complete response (CR), 24 (36.92%) patients had partial response (PR), 30 (46.15%) patients achieved stable disease (SD), and 10 (15.38%) patients had progression disease (PD), resulting in an ORR of 38.46% and DCR of 84.62%. The most common AE was diarrhea (84.17%), but only 5 (4.17%) patients were reported grade ≥ 3 diarrhea which could be well controlled. Other AEs with an incidence higher than 20.00% were anemia (36.67%), leukopenia (25.83%), vomiting (25.00%), neutropenia (22.50%). No treatment-related death occurred. Conclusions: Pyrotinib demonstrated an encouraging efficacy and manageable safety in patients with advanced HER2+ breast cancer. More data would be analyzed and reported in the future. Clinical trial information: ChiCTR1900021819.

Estrogen receptor (ER), Ki-67, p27Kip1, and histologic grade as predictors of pathologic complete response (pCR) in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC) using fluorouracil, epirubicin, and cyclophosphamide (FEC), taxanes, and trastuzumab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 613-613
Author(s):  
Sasagu Kurozumi ◽  
Kenichi Inoue ◽  
Hiroyuki Takei ◽  
Hiroshi Matsumoto ◽  
Takashi Yoshida ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Histological Grade ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Her2 Positive ◽  
Ki 67 ◽  
Prognostic Effect ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

613 Background: NAC with taxanes and FEC concurrently with trastuzumab is a potent regimen in patients with HER2-positive breast cancer (BC). Several studies revealed high pCR rates in BC patients treated with this regimen; however, predictive factors and a prognostic effect of pCR have been still unclear. In this study, we analyzed several factors including p27Kip1 (cyclin-dependent kinase inhibitor acting as tumor suppressor) for correlation with pCR. We also evaluated differences in recurrence-free survival (RFS) or overall survival (OS) between patients with pCR and non-pCR, and with positive and negative nodes after NAC. Methods: Our study included 129 Japanese women with invasive, HER2-positive BC who received 12 cycles of paclitaxel or 4 cycles of docetaxel followed by 4 cycles of FEC-75 with concomitant trastuzumab for 24 weeks. We analyzed the correlation of pCR (no invasive lesions in the breast) and nodal status after NAC with RFS and OS, and analyzed the baseline expressions of ER, Ki-67, and p27Kip1, and histological grade for correlation with pCR. Positive or high expression was defined by nuclear labeling index: ER ≥10%, p27Kip1 ≥75%, Ki-67 ≥30%. Results: In 129 patients, pCR was found in 85 (66%). Patients with pCR after NAC had significantly better RFS than those without pCR (median follow-up: 41 months). Furthermore, patients with pathologically negative nodes after NAC had significantly better OS than those with pathologically positive nodes. Negative ER (79% vs. 40%), high Ki-67 (72% vs. 47%), low p27Kip1 (71% vs. 50%), and histological grade 3 (70% vs. 39%) were significant predictors of pCR. Conclusions: In patients with HER2-positive BC, this regimen was effective achieving the high pCR rate. pCR and pathologically negative nodes after NAC were predictive of RFS and OS, respectively. The expressions of ER, Ki-67, and p27Kip1, and histological grade at baseline were predictive of pCR. p27Kip1, a new predictor of pCR after NAC needs to be further analyzed.

Neratinib for the treatment of early-stage, hormone receptor-positive, HER2-overexpressed breast cancer

2020 ◽  
Vol 16 (17) ◽  
pp. 1165-1177
Author(s):  
Yolanda Jerez ◽  
Blanca Herrero ◽  
Marta Arregui ◽  
Blanca Morón ◽  
Miguel Martín ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Future Directions ◽  
Her2 Positive Breast Cancer ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

HER2-positive breast cancer accounts for 18–20% of all breast cancers. Despite significant advances and the currently available adjuvant treatments for management of the disease, approximately 25% of HER2-positive early-stage breast cancer patients show relapse and die. Neratinib is an irreversible tyrosine kinase inhibitor. Multiple studies have reported its significant antitumor activity in metastatic HER2-positive breast cancer. It is administered orally and has also been tested in the adjuvant setting. In this article, we present a comprehensive review of the pharmacokinetics and pharmacodynamics of neratinib as well as its clinical efficacy, with an emphasis on early HER2-positive breast cancer and suggestions for future directions for neratinib research.

scholarly journals Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients

Breast Care ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. 401-408 ◽  
Author(s):  
Lidia Kowalczyk ◽  
Rupert Bartsch ◽  
Christian F. Singer ◽  
Alex Farr
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Targeted Therapies ◽  
Kinase Inhibitor ◽  
Trastuzumab Emtansine ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Anti Tumor Activity ◽  
Positive Breast Cancer

The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.

scholarly journals The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1329
Author(s):  
Nathan Griffin ◽  
Mark Marsland ◽  
Severine Roselli ◽  
Christopher Oldmeadow ◽  
John Attia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Tyrosine Kinase Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Ductal Carcinomas ◽  
Positive Breast Cancer

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.

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