Gefitinib in Combination with Weekly Docetaxel in Patients with Metastatic Breast Cancer Caused Unexpected Toxicity: Results from a Randomized Phase II Clinical Trial

In patients with metastatic breast cancer, taxane treatment demonstrates activity but is not curative. Targeted treatment modalities are therefore necessary in order to improve outcomes in this group. A randomized placebo-controlled phase II trial was initiated to evaluate effect and toxicity of gefitinib (250 mg QD) and docetaxel 35 mg/m2 (six of seven weeks) (NCT 00319618). The inclusion of 66 patients was planned. The study was closed due to treatment-related toxicity. Of the 18 included patients, seven (of which three received gefitinib) were withdrawn from the study due to toxicity. Of the nine patients receiving gefitinib and chemotherapy, one achieved a partial response and four stable disease. In the chemotherapy of nine patients, four had a partial response and four stable disease. The breast cancer patients in this study were genotyped using a panel of 14 single-nucleotide polymorphisms (SNPs), previously found associated with docetaxel clearance in a cohort of lung cancer patients. We were unable to identify genes related to toxicity in this study. Nevertheless, toxicity was aggravated by the addition of the tyrosine kinase inhibitor. In conclusion, despite adequately tolerated as monotherapy, combination regimens should be carefully considered for overlapping adverse events in order to avoid increased treatment-related toxicity

High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer

Peer reviewe

Detection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screen

publishedVersio

Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models

<p>Abstract</p> <p>Background</p> <p>Increased concentrations of choline-containing compounds are frequently observed in breast carcinomas, and may serve as biomarkers for both diagnostic and treatment monitoring purposes. However, underlying mechanisms for the abnormal choline metabolism are poorly understood.</p> <p>Methods</p> <p>The concentrations of choline-derived metabolites were determined in xenografted primary human breast carcinomas, representing basal-like and luminal-like subtypes. Quantification of metabolites in fresh frozen tissue was performed using high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS).</p> <p>The expression of genes involved in phosphatidylcholine (PtdCho) metabolism was retrieved from whole genome expression microarray analyses.</p> <p>The metabolite profiles from xenografts were compared with profiles from human breast cancer, sampled from patients with estrogen/progesterone receptor positive (ER+/PgR+) or triple negative (ER-/PgR-/HER2-) breast cancer.</p> <p>Results</p> <p>In basal-like xenografts, glycerophosphocholine (GPC) concentrations were higher than phosphocholine (PCho) concentrations, whereas this pattern was reversed in luminal-like xenografts. These differences may be explained by lower choline kinase (<it>CHKA</it>, <it>CHKB</it>) expression as well as higher PtdCho degradation mediated by higher expression of phospholipase A2 group 4A (<it>PLA2G4A</it>) and phospholipase B1 (<it>PLB1</it>) in the basal-like model. The glycine concentration was higher in the basal-like model. Although glycine could be derived from energy metabolism pathways, the gene expression data suggested a metabolic shift from PtdCho synthesis to glycine formation in basal-like xenografts. In agreement with results from the xenograft models, tissue samples from triple negative breast carcinomas had higher GPC/PCho ratio than samples from ER+/PgR+ carcinomas, suggesting that the choline metabolism in the experimental models is representative for luminal-like and basal-like human breast cancer.</p> <p>Conclusions</p> <p>The differences in choline metabolite concentrations corresponded well with differences in gene expression, demonstrating distinct metabolic profiles in the xenograft models representing basal-like and luminal-like breast cancer. The same characteristics of choline metabolite profiles were also observed in patient material from ER+/PgR+ and triple-negative breast cancer, suggesting that the xenografts are relevant model systems for studies of choline metabolism in luminal-like and basal-like breast cancer.</p

Triple-Negative Breast Cancer and the Need for New Therapeutic Targets

Triple-negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER2 gene. The majority of the tumors classified as TNBCs are highly malignant, and only a subgroup responds to conventional chemotherapy with a favorable prognosis. Results from decades of research have identified important molecular characteristics that can subdivide this group of breast cancers further. High-throughput molecular analyses including sequencing, pathway analyses, and integrated analyses of alterations at the genomic and transcriptomic levels have improved our understanding of the molecular alterations involved in tumor development and progression. How this knowledge should be used for rational selection of therapy is a challenging task and the subject of numerous ongoing research programs. This review summarizes the current knowledge on the clinical characteristics and molecular alterations of TNBCs. Currently used conventional therapeutic strategies and targeted therapy studies are discussed, with references to recently published results on the molecular characterization of TNBCs

Evaluation of caspase activation after lexatumumab (1 µg/ml) and DTIC (50 µg/ml) treatment in FEMX-1 and HHMS.

<p>The cells were harvested 24 h (Western blot) or 48 h (Caspase activity) after treatment exposure and analyzed for various apoptotic markers. (A) Immuno-blot detection of caspase-8, −3 and −7 and PARP cleavage. (B) Caspase 3/7 activity. Results are expressed relative to untreated control cells and normalized to the cell number in the sample. Data are presented as mean ± standard error of the mean (SEM) of three parallel experiments. (C) Immuno-blot detection of Bid and caspase-9 cleavage. β-actin is used as loading control in (A) and (C). Cell lysates were prepared from three independent biological experiments, and representative blots are included in the figure.</p

The growth reducing capacity of the combination treatment in vivo.

<p>FEMX-1 xenografts were treated with lexatumumab (L) (10 mg/kg, twice a week, i.v. injection), IgG isotype control (10 mg/kg, twice a week, i.v. injection), DTIC (D) ((A) 62.5 mg/kg or (B) 125 mg/kg once a week, i.p. injection) or the combination of the Abs and DTIC. Treatment time is indicated in the figure by arrows. The tumor volumes were measured twice a week using a caliper, and are presented as relative tumor volume related to the volume of the tumor at the initiation of the treatment. At least eight tumors are included in each treatment group.</p