Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

Nielsen, Dorte; Kümler, Iben; Palshof, Jesper Andreas; Andersson, Michael

doi:10.1016/j.breast.2012.09.008

Cited by 88 publications

(77 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HER2 is amplified and overexpressed in 15% to 20% of breast cancers (2). Trastuzumab, a HER2-targeting mAb, has become the mainstay of therapy in the palliative and adjuvant or neoadjuvant settings for patients with HER2-positive breast cancer since its first approval in 1998 (3). However, HER2-positive breast cancer may be intrinsically, or may become, resistant to trastuzumab in around 70% of cases (4).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Ring

Wheatley

Hatcher

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer.Experimental Design: This phase I study used a 3þ3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible.Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0-274.0).Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug-drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted.

show abstract

Section: Introductionmentioning

confidence: 99%

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Ring

Wheatley

Hatcher

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Despite the success of trastuzumab combined with chemotherapy, approximately 30-50% of patients with naïve HER2+ MBC do not achieve an objective response in the first-line setting indicating de novo resistance to trastuzumab, and TTP as well as survival remains short (7-17 months, 22-38 months, respectively) [Slamon et al 2001;Baselga et al 2012;Nielsen et al 2013;Swain et al 2013] (Table 1).This had led to intense interest in the development of alternative (Continued) approaches to block signaling through the HER2 pathway, with resulting significant improvements in outcome as outlined below.…”

Section: Trastuzumabmentioning

confidence: 99%

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options

Jiang

Rugo

2015

Ther Adv Med Oncol

View full text Add to dashboard Cite

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) remains an incurable disease, and approximately 25% of patients with HER2+ early breast cancer still relapse after adjuvant trastuzumab-based treatment. HER2 is a validated therapeutic target that remains relevant throughout the disease process. Recently, a number of novel HER2 targeted agents have become available, including lapatinib (a small molecule tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor), pertuzumab (a new anti-HER2 monoclonal antibody) and ado-trastuzumab emtansine (T-DM1, a novel antibody-drug conjugate), which provide additional treatment options for patients with HER2+ MBC. The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or T-DM1 compared with standard HER2 targeted therapy. Here we review the clinical development of approved and investigational targeted agents for the treatment of HER2+ MBC, summarize the latest results of important clinical trials supporting use of these agents in the treatment of HER2+ MBC, and discuss how these results impact therapeutic options in clinical practice.

show abstract

“…However, subsets of patients do not respond to these treatments, even in the presence of their targets or develop resistance after initial response [3,4]. Since the threshold for labelling breast tumors as positive for hormone receptors is set at 1 % and that for HER2 at 10 %, it is not surprising that tumors labelled positive for certain markers may have a variable proportion of positive cells.…”

Section: Introductionmentioning

confidence: 99%

Single Section Biomarker Measurement and Colocalization via a Novel Multiplexing Staining Technology

et al. 2016

View full text Add to dashboard Cite

Abstract. Measuring colocalization of multiple biomarkers may contribute to understanding tumor growth and progression. Traditionally, multiple biomarkers colocalization has been performed by processing multiple serial tissue sections. To provide true colocalization measures, we are investigating single section multiplexing techniques. Utilizing a fluorescent-based sequential stain and bleach system (SSB) we investigated multiplexing 8 markers in breast cancer tissue microarray sections. The experiments consisted of a 4 predictive biomarker panel (ER, PR, HER2, and Ki67) and markers to assist in the image processing. The goals included comparing the immunofluorescent signal with bright field single chromogen IHC scores, the measurements of tumor heterogeneity, and to discover technical challenges. Early results suggest that SSB signals correspond to traditional IHC staining. Additionally, our work has highlighted improvements to workflow and the staining process. We present a review of our progress and expectations for this technology.

show abstract

Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

Cited by 88 publications

References 84 publications

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options

Single Section Biomarker Measurement and Colocalization via a Novel Multiplexing Staining Technology

Contact Info

Product

Resources

About