A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2- negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene: a study protocol

Kümler, Iben; Balslev, Eva; Stenvang, Jan; Brünner, Nils; Nielsen, Dorte

doi:10.1186/s12885-015-1072-9

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…The efficiency and cytotoxic effect of the CPT may be regulated by other means than TOP1 expression and activity. Hence, the large variation in CPT response rates observed in small and non-randomized trials for BC may be due, at least in part, to a lack of reliable selective parameters for patient stratification [56].…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study

et al. 2019

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BackgroundCamptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes.MethodWe evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC.ResultsIn all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives.ConclusionTOP1 activity is not a marker for CPT sensitivity in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study

et al. 2019

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“…As an example, the pooled analysis of the Side Out 1 and 2 trials identified TOPO1 as a protein frequently overexpressed in MBC and as a potential predictor of response to irinotecan‐based treatment, as previously described [ 21 , 22 , 23 , 24 , 25 ]. Irinotecan as a single agent, when given after an anthracycline or taxane, has an objective response rate of 14% when given every 3 weeks and 23% when given weekly [ 26 ].…”

Section: Discussionmentioning

confidence: 88%

Multi‐omic molecular profiling guide’s efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial

et al. 2021

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This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.

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“…Data for TOP1-poisons in breast cancer is limited. Phase II trials in refractory patients have shown response rates similar to anthracyclines (30%) and taxanes (12%) versus 5–25% for irinotecan 30 , without stratifying patients. Our factor 12 points to tumors that are driven by ERBB-family members, growth factors, and hormone receptors (ESR1/AR).…”

Section: Resultsmentioning

confidence: 99%

Genomic data integration by WON-PARAFAC identifies interpretable factors for predicting drug-sensitivity in vivo

et al. 2019

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Integrative analyses that summarize and link molecular data to treatment sensitivity are crucial to capture the biological complexity which is essential to further precision medicine. We introduce Weighted Orthogonal Nonnegative parallel factor analysis (WON-PARAFAC), a data integration method that identifies sparse and interpretable factors. WON-PARAFAC summarizes the GDSC1000 cell line compendium in 130 factors. We interpret the factors based on their association with recurrent molecular alterations, pathway enrichment, cancer type, and drug-response. Crucially, the cell line derived factors capture the majority of the relevant biological variation in Patient-Derived Xenograft (PDX) models, strongly suggesting our factors capture invariant and generalizable aspects of cancer biology. Furthermore, drug response in cell lines is better and more consistently translated to PDXs using factor-based predictors as compared to raw feature-based predictors. WON-PARAFAC efficiently summarizes and integrates multiway high-dimensional genomic data and enhances translatability of drug response prediction from cell lines to patient-derived xenografts.

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A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2- negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene: a study protocol

Cited by 9 publications

References 39 publications

Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study

Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study

Multi‐omic molecular profiling guide’s efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial

Genomic data integration by WON-PARAFAC identifies interpretable factors for predicting drug-sensitivity in vivo

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