title: Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.
abstract: Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially “actionable” biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those “profiled” patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 “profiled” patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required to successfully enroll “profiled” patients with metastatic breast cancer in early clinical trials stratified by exploratory biomarkers.
authors.forename: Anja
authors.initials: A
authors.lastname: Welt
authors.forename: Mitra
authors.initials: M
authors.lastname: Tewes
authors.forename: Bahriye
authors.initials: B
authors.lastname: Aktas
authors.forename: Oliver
authors.initials: O
authors.lastname: O Hoffmann
authors.forename: Marcel
authors.initials: M
authors.lastname: Wiesweg
authors.forename: Saskia
authors.initials: S
authors.lastname: Ting
authors.forename: Henning
authors.initials: H
authors.lastname: Reis
authors.forename: Karl
authors.initials: K
authors.lastname: Worm
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.forename: Jörg
authors.initials: J
authors.lastname: Hense
authors.forename: Michael R
authors.initials: MR
authors.lastname: Palmer
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Johanna
authors.initials: J
authors.lastname: Wendling
authors.forename: Josef
authors.initials: J
authors.lastname: Kossow
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.forename: Cathrin
authors.initials: C
authors.lastname: Lehnerdt
authors.forename: Marzena
authors.initials: M
authors.lastname: Kohl
authors.forename: Cordula
authors.initials: C
authors.lastname: Derks
authors.forename: Silke
authors.initials: S
authors.lastname: Skottky
authors.forename: Ulrike
authors.initials: U
authors.lastname: Haus
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor