Refractory HER2-positive Breast Cancer Research Articles

A quantitative systems pharmacological approach identified activation of JNK signaling pathway as a promising treatment strategy for refractory HER2 positive breast cancer

HER2-positive breast cancer (BC) is a rapidly growing and aggressiveBC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitativesystems pharmacological (QSP) approach to evaluate the efficacy of lapatinib (LAP), abemaciclib (ABE) and 5-fluorouracil (5-FU) mono- and combination therapies in JIMT-1 cells, a HER2+ BC cell line exhibiting intrinsic resistanceto trastuzumab. Concentration-response relationships and temporal profiles of cellular viability were assessed upon exposure to single agents and theircombinations. To quantify the nature and intensity of drug-drug interactions, pharmacodynamic cellular response models were generated, to characterize single agent and combination time course data. Temporal changes in cell-cycle phase distributions, intracellular protein signaling, and JIMT-1 cellular viability were quantified, and a systems-based protein signaling network model was developed, integrating protein dynamics to drive the observed changes in cell viability. Global sensitivity analyses for each treatment arm were performed, to identify the most influential parameters governing cellular responses. Our QSP model was able to adequately characterize protein dynamic and cellular viability trends following single and combination drug exposure. Moreover, the model and subsequent sensitivity analyses suggest that the activation of the stress pathway, through pJNK, has the greatest impact over the observed declines of JIMT-1 cell viability in vitro. These findings suggest that dual HER2 and CDK 4/6 inhibition may be a promising novel treatment strategy for refractory HER2+ BC, however, proof-of-concept in vivo studies are needed to further evaluate the combined use of these therapies.

Drug Brings Marked Responses in Refractory HER2-Positive Breast Cancer

Drug Brings Marked Responses in Refractory HER2-Positive Breast Cancer

Abstract CS1-2: Emerging Therapies for HER2 Positive Breast Cancer

Abstract HER2 targeted therapies have had a significant impact in improving clinical outcomes and survival for patients with HER2 positive breast cancer. However, new therapies for patients with refractory disease are still needed. Based on a greater understanding of the biology and mechanisms of resistance, a new generation of HER2 agents is evolving. Here we provide an overview of promising novel therapies, both proven and in development, for the treatment of refractory HER2 positive breast cancer. This will include a review of antibody drug conjugates, tyrosine kinase inhibitors, immune strategies as well as future combination therapies. Citation Format: S Modi. Emerging Therapies for HER2 Positive Breast Cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr CS1-2.

Abstract P2-09-21: Molecular alterations and poziotinib, a pan-HER inhibitor efficacy in human epidermal growth factor receptor 2(HER2) positive breast cancers: Combined exploratory biomarker analysis from phase II clinical trial of poziotinib for refractory HER2 positive breast cancer(BC) patients

Abstract Introduction: Poziotinib is a novel, pan-HER kinase inhibitor which showed potent anti-tumor activities through irreversible inhibition of HER family tyrosine kinases in preclinical and early clinical studies. Recent the open-label, multicenter phase II trial of poziotinib monotherapy evaluated that poziotinib is a new promising option for patients with HER2-positive metastatic BC who have failed more than two HER2 targeted therapy (NCT02418689). We evaluated genetic profiles of HER2-positive metastatic BC and investigated potential biomarkers of poziotinib for HER2-positive metastatic BC (MBC). Methods: All participants were diagnosed as HER2-positive BCs according to American Society of Clinical Oncology/College of American Pathologists HER2 guideline and provided tissue specimens that would be possible to extract DNA and RNA for next generation sequencing. We performed targeted deep sequencing with a customized 381 cancer gene panel (CancerSCAN™) and analyzed the relationship among the sequencing data, immunohistochemistry and clinical outcome. Results: From Apr 2015 to Feb 2016, 106 patients were enrolled in the trial from 7 institutes in Korea. Of 106 patients, biomarker data were available for 79 patients. TP53 was the most frequently mutated gene (70.8%) followed by PIK3CA (45.6%). HER2 single nucleotide variant (SNV) was detected in 13 BCs (16.5%) and HER3 SNV was in 9 (11.4%). The score of HER2 immunohistochemistry (IHC) was 3+ in 68 BCs and 2+ with positive in situ hybridization in 11 BCs. In copy number variant (CNV) analysis, HER2 amplification (86.1%) was most frequently observed and followed by CDK12 amplification (58.2%) and APOBEC3B deletion (30.4%). IHC score of HER2 was positively correlated to copy number (CN) of HER2 (P=0.001) but 11 breast cancer tissue did not have copy number amplification of HER2 (13.9%) (Six of HER2 IHC score 2+ and 5 of 3+). The median progression free survival (PFS) was 4.04 months (95% CI, 2.96 - 4.40) for patients who treated with poziotinib in this study. PIK3CA activating mutations were associated with short PFS compared to wild type (WT) and other SNVs (Median PFS of activating mutations vs. WT and others: 2.66 vs. 4.40 (months), P=0.009). HER2 CN amplification was positively correlated to duration of PFS (Median PFS of no amplification vs. 4 ≤ CN < 16 vs. 16 ≤ CN: 2.56 vs. 3.02 vs. 4.86 (months), P=0.032). HER2 SNVs prolonged duration of PFS without statistical significance (Median PFS of HER2 SNVs vs. WT: 4.24 vs. 3.19 (months), P=0.114), but 10 of 13 BCs with HER2 SNV (76.9%) had clinical benefit from poziotinib and 5 BCs (38.5%) had durable response more than 6 months. Conclusion: In this biomarker analysis, SNV of HER2 was frequently observed in HER2 positive MBCs and HER2 CN amplification was detected not in all. High CN amplification of HER2 derived longer PFS than those with low CN. To contrary to this, activating PIK3CA mutations shorten PFS compared to those with WT. In addition, HER2 SNVs might be a potential biomarker of poziotinib in HER2-positive MBC. Further functional study would be warranted. Citation Format: Kim J-Y, Lee E, Park K, Jung HH, Park W-Y, Lee K-H, Sohn JH, Lee KS, Jung KH, Kim J-H, Lee KH, Im S-A, Park YH. Molecular alterations and poziotinib, a pan-HER inhibitor efficacy in human epidermal growth factor receptor 2(HER2) positive breast cancers: Combined exploratory biomarker analysis from phase II clinical trial of poziotinib for refractory HER2 positive breast cancer(BC) patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-21.