poziotinib and Breast-Neoplasms

We aimed to investigate the impact of genetic alterations on the efficacy of poziotinib in a phase II clinical trial of patients with heavily treated HER2-positive metastatic breast cancer (BC). We performed targeted ultra-deep sequencing with a customized cancer gene panel and RNA expression assay using BC specimens. Of 106 patients, biomarker data were available for 85. Copy number (CN) amplifications of HER2 were observed in 72 patients (85%), and CN >8 in 50 (59%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%). Genetic alterations of PIK3CA pathway were found in 40 patients (47%). Median progression free survival (PFS) of the biomarker analysis group was 3.61 months. In terms of PFS, HER2 with CN >8 prolonged (hazard ratio (HR) 0.61, 95% CI: 0.38, 0.97, p = 0.037) and alteration of PIK3CA pathway shortened the duration of survival (HR 2.25, 95% CI: 1.39, 3.63, p = 0.001). SNVs of HER2 increased survival duration, but the effect was not significant (HR: 0.58, 95% CI: 0.31, 1.08, p = 0.085). In addition, SNVs in the ERBB3 cytoplasmic domain decreased poziotinib response (HR: 4.58, 95% CI: 2.02, 10.37, p < 0.001). In multigene analysis, BC with HER2 CN >8 and intact PIK3CA pathway had significantly longer PFS compared to others (HR: 0.37, 95% CI: 0.21, 0.66, p = 0.001), while SNVs in the ERBB3 cytoplasmic domain predicted poor prognosis (HR: 4.28, 95% CI: 1.71, 10.71, p < 0.001). In conclusion, HER2 CN amplification, PIK3CA pathway alteration, and ERBB3 cytoplasmic mutation showed predictive roles on clinical outcomes of HER2-positive MBC treated with poziotinib.

Topics: Adult; Algorithms; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Exons; Female; Gene Expression; High-Throughput Nucleotide Sequencing; Humans; Middle Aged; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2

Although the introduction of human epidermal growth factor receptor (HER)2-directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2-positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies. Patients received 12 mg poziotinib once daily on a 14-day on/7-day off schedule. Progression-free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30-76) and had received a median of four prior therapies including two HER2-directed therapies for advanced or metastatic cancers. The median follow-up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94-4.40 months), and median overall survival has not been reached. The most common treatment-related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Recurrence; Republic of Korea; Survival Analysis

The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2-mutant metastatic breast cancer.. Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.

Topics: Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Protein Kinase Inhibitors; Quinazolines; Quinolines; Receptor, ErbB-2

We explored clinical implication of intrinsic molecular subtype in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer (BC) with pan-HER inhibitor from a phase II clinical trial of poziotinib in refractory HER2+BC patients.. For this translational research correlated with phase II clinical trial, we performed an nCounter expression assay, using gene panel including 50 genes for PAM50 prediction and targeted deep sequencing.. From 106 participants, we obtained 97 tumor tissues and analyzed gene expression in 91 of these samples. Of 91 HER2+BCs, 40 (44.0%) were HER2-enriched (E) intrinsic molecular subtype, 17 (18.7%) of Luminal A, 16 (17.6%) of Basal-like, 14 (15.4%) of Luminal B and 4 (4.4%) of Normal-like. HER2-E subtype was associated with hormone receptor negativity (odds ratio [OR] 2.93; p = 0.019), 3 + of HER2 immunohistochemistry(IHC) (OR 5.64; p = 0.001), high mRNA expression of HER2 (OR 14.43; p = 0.001) and copy number(CN) amplification of HER2 (OR 12.80; p = 0.005). In genetic alterations, alteration was more frequently observed in HER2-E subtype (OR 3.84; p = 0.022) but there was no association between PIK3CA alteration and HER2-E subtype (p = 0.655). In terms of drug efficacy, high mRNA expression of HER2 was the most powerful predictor of poziotinib response (median progression-free survival [PFS): 4.63 months [high] vs. 2.56 [low]; p < .001). In a combination prediction model, median PFS of intrinsic subtypes except Her2-E with high HER2 mRNA expression without PIK3CA genetic alteration was 6.83 months and that of the remaining group was 1.74 months (p < .001).. HER2-E subtype was associated with hormone receptor status, HER2 IHC, CN and mRNA expression and TP53 mutation. In survival analysis, the information of level of HER2 mRNA expression, intrinsic molecular subtype and PI3K pathway alteration would be independent predictors to poziotinib treatment. ClinicalTrials.gov identifier: NCT02418689.

Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Phosphatidylinositol 3-Kinases; Prognosis; Quinazolines; Receptor, ErbB-2; RNA, Messenger

Topics: Breast Neoplasms; Drug Resistance, Neoplasm; Exons; Female; Humans; Mutation; Phyllodes Tumor; Prognosis; Quinazolines; Receptor, ErbB-2

HM781-36B is an orally administered pan-human epidermal growth factor receptor (HER) inhibitor. To explore the role of pan-HER inhibitor in breast cancer, we investigated the antitumor effect and mechanisms of HM781-36B in breast cancer cell lines. Six breast cancer cell lines (BT474, MDA-MB-453, SK-BR-3, T47D, MCF-7, and MDA-MB-231) were tested. The growth inhibitory effect was assessed using the tetrazolium bromide [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] assay. The cell cycle at various concentrations of HM781-36B was analyzed by flow cytometry, and analysis of downstream molecules was performed by western blot analysis. Interaction of HM781-36B with cytotoxic chemotherapeutic agents was analyzed by combination index using CalcuSyn. The HER2-amplified cells (SK-BR-3, BT474, and MDA-MB-453) were sensitive to HM781-36B (IC50=0.001 μmol/l, 0.0012 μmol/l, and 0.0095 μmol/l, respectively). HM781-36B induced G1 arrest and resulted in apoptosis. It reduced the level of p-HER2, p-AKT, p-ERK, and p-STAT3. HM781-36B combined with 5-fluorouracil, cisplatin, paclitaxel, or gemcitabine showed a synergistic inhibitory effect on the HER2-amplified and on some of the HER2-nonamplified breast cancer cells. HM781-36B could be a promising treatment for HER2-amplified breast cancer as a single agent or in combination with cytotoxic agents and can be a candidate for treatment of HER2-nonamplified breast cancer in combination with cytotoxic agents.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Gemcitabine; Humans; Mitochondria; Paclitaxel; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Receptor, ErbB-2; STAT3 Transcription Factor