Abstract
BackgroundGreater understanding of the molecular classification of breast cancer has permitted the development of rational drug design strategies. In a phase I clinical trial setting, molecular profiling with next-generation sequencing of individual tumour samples has been employed to guide treatment.MethodsWe conducted a retrospective evaluation of clinical outcomes of patients with metastatic breast cancer (MBC) treated in phase I clinical trials at our institution to assess the benefit of molecularly matched compared to non-matched treatments.ResultsA total of 97 consecutive patients with MBC were enrolled onto ≥1 trial between 2009 and 2015. Fourteen patients participated in multiple trials, and a total of 113 trial encounters were reviewed in this retrospective study. Eighty-three percent of patients with molecular data available were able to participate in trials matched to molecular aberrations. Patients who were treated on matched studies had improved clinical benefit (RR: 1.80, p = 0.005), progression-free (HR: 0.52, p = 0.003) and overall survival (HR: 0.54, p < 0.001). Treatment was well tolerated with low rates of treatment discontinuation for toxicity (8% overall) that did not differ between groups. No toxicity-related deaths were observed.ConclusionsMolecular profiling for MBC patients in a phase I setting is feasible and aids therapeutic decisions with improved patient outcomes.
Highlights
Greater understanding of the molecular classification of breast cancer has permitted the development of rational drug design strategies
Our study of patients with metastatic breast cancer (MBC) treated in a phase I clinical trial setting reported results consistent with previous publications.[8]
When molecular data were available, a large proportion of patients were able to undergo successful matching (83%), and patients treated on matched studies had improved patient outcomes
Summary
Greater understanding of the molecular classification of breast cancer has permitted the development of rational drug design strategies. In breast cancer, targeted therapies against mTOR (everolimus, Novartis) and CDK4/6 (palbociclib, Pfizer) have been granted regulatory approval for treatment, predictive biomarker analyses have not demonstrated statistically significant correlations between candidate biomarkers and treatment outcomes.[1,2] The use of molecular profiling of individual tumour samples from patients with breast cancers to guide treatment choice has become more feasible with improved and more cost-efficient genomic next-generation sequencing (NGS) techniques, and studies have provided proof of concept that such a personalised approach is a rational strategy in cancer medicine and may lead to improved patient outcomes.[3,4] In an early-phase clinical trial setting where there is a dearth of data in guiding treatment choice, molecular profiling may have an important role in guiding physicians in making rational treatment decisions based on the scientific knowledge of the underlying cancer biology matched with the molecular pharmacology of the antitumor agent In this retrospective study, we evaluated the clinical outcomes of patients with metastatic breast cancer (MBC) treated within a dedicated phase I clinical trials unit at our institution. The primary aim of the study was to assess the benefit of molecularly matched therapy compared to non-matched therapy, with secondary objectives of reporting the prevalence of molecular aberrations among these patients, as well as the safety and tolerability of these agents in a phase I setting
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