Two open-label, single arm, non-randomized phase II studies of irinotecan for the treatment of metastatic breast cancer in patients with increased copy number of the topoisomerase I gene.
Aged
Antineoplastic Agents
/ therapeutic use
Biomarkers, Pharmacological
Breast Neoplasms
/ diagnosis
DNA Topoisomerases, Type I
/ genetics
Drug Therapy, Combination
Female
Gene Dosage
Humans
Irinotecan
/ therapeutic use
Middle Aged
Predictive Value of Tests
Prognosis
Receptor, ErbB-2
/ metabolism
Topoisomerase I Inhibitors
/ therapeutic use
Trastuzumab
/ therapeutic use
Treatment Outcome
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
13 Jun 2019
13 Jun 2019
Historique:
received:
23
08
2018
accepted:
31
05
2019
entrez:
15
6
2019
pubmed:
15
6
2019
medline:
24
12
2019
Statut:
epublish
Résumé
Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan. Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/- trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months. The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD. The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC. Eudract registration numbers 2012-002348-26 and 2012-002347-23 . Registration date August 20th 2012.
Sections du résumé
BACKGROUND
BACKGROUND
Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan.
METHODS
METHODS
Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/- trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months.
RESULTS
RESULTS
The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD.
CONCLUSIONS
CONCLUSIONS
The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC.
TRIAL REGISTRATION
BACKGROUND
Eudract registration numbers 2012-002348-26 and 2012-002347-23 . Registration date August 20th 2012.
Identifiants
pubmed: 31196001
doi: 10.1186/s12885-019-5788-9
pii: 10.1186/s12885-019-5788-9
pmc: PMC6567440
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Pharmacological
0
Topoisomerase I Inhibitors
0
Irinotecan
7673326042
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
DNA Topoisomerases, Type I
EC 5.99.1.2
Trastuzumab
P188ANX8CK
Types de publication
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
573Subventions
Organisme : Kræftens Bekæmpelse
ID : R56-Rp6818
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