Ignite Creation Date:
2024-05-05 @ 11:53 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00162812
Status:
TERMINATED
Last Update Posted:
2008-07-18
First Post:
2005-09-09
Brief Title:
Topoisomerase II Alpha Gene Amplification and Protein Overexpression Predicting Efficacy of Epirubicin
Sponsor:
Jules Bordet Institute
Organization:
Jules Bordet Institute
Study Overview
Official Title:
Prospective Evaluation of Topoisomerase II Alpha Gene Amplification and Protein Overexpression as Markers Predicting the Efficacy of Epirubicin in the Primary Treatment of Breast Cancer Patients
Status:
TERMINATED
Status Verified Date:
2008-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Low accrual rate
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TOP
Brief Summary:
prospective evaluation of topoisomerase II alpha gene amplification and protein overexpression as markers predicting the efficacy of epirubicin in the primary treatment of breast cancer patients
Detailed Description:
Clinical evaluation of topo II a as a predictive marker Preliminary results from a clinical study suggest that complete remission after treatment with anthracyclines for advanced breast cancer is observed only in case of topo II a gene amplification 7 complete remissions all in patients with topo II a gene amplified tumors no complete remissions in patients with a normal or deleted topo II a gene
Moreover our group has analyzed the predictive value of topo II a in a population of node-positive breast cancer patients randomly treated either with anthracyclines or with CMF Belgian cooperative trial In a first study topo II a was evaluated by immunohistochemistry which allows the detection of topo II a protein expression The results of this study suggested that patients deriving the highest benefit from anthracyclines were those in which topo II a protein is immunostained in more than 10 of tumor cells The main findings of this study should be seen as hypothesis-generating because of the limited number of patients evaluated about fifty in each study arm and because topo II a protein levels depend on gene amplification as well as on tumor proliferation rate Therefore topo II a protein expression does not necessarily reflect topo II a gene status
The second study run by our group was based on the same series of patients evaluated in the first study but this time both HER-2 and topo II a genes were evaluated by fluorescence in-situ hybridization FISH which allows the detection of gene aberrations The main findings of the second study were quite consistent with the pre-clinical data suggesting that only HER-2 amplifiedtopo II a amplified tumours show great sensitivity to anthracyclines while the efficacy of these same agents in HER-2 amplifiedtopo II a non-amplified tumors is comparable to the efficacy of other drugs or regimens like CMF
Nevertheless although the results reported in this study bring some additional support to the hypothesis of topo II a as a marker predicting the efficacy of anthracyclines no definitive conclusions can be drawn because of the fairly limited number of patients evaluated and the retrospective nature of the analyses
The present study protocol Supported by in-vitro and preliminary in-vivo data briefly summarized above this study is designed to test prospectively the value of topo II alpha gene amplification and protein overexpression in predicting the efficacy of anthracyclines To our knowledge this is the only prospective trial worldwide which is attempting to prospectively clarify the predictive value of this interesting biological marker This study could have important practical implications in the daily clinical management of early breast cancer patients because if the trial confirms that topo II a gene amplification andor protein overexpression are associated with high efficacy of anthracyclines while topo II a normaldeleted gene and low protein content are associated with modest efficacy an important step forward in the direction of anthracycline tailoring would be accomplished
The practical advantage of this approach would be to use anthracyclines primarily in patients who are supposed to derive the largest benefit thus sparing the long-term anthracycline-related toxicity ie secondary acute myeloid leukemia cardiac dysfunction and amenorrheasterility in case of fertile women to those patients for whom no significant gain in antitumor activity is anticipated
To reach this ambitious aim early breast cancer patients with tumors of at least 2 cm defined by breast ultrasound will be evaluated for topo II a gene and protein expression For this purpose a pre-treatment biopsy tru-cut will be performed and topo II a gene will be evaluated on fixed samples by FISH The use of a triple probe will allow the concomitant evaluation of the HER-2 gene status Topo II a protein will be evaluated by immunohistochemistry IHC Afterwards all patients independently of the topo II a gene and protein status will be treated with single-agent epirubicin Eligibility criteria will allow the participation of patients for whom the use of an anthracycline-based adjuvant therapy would have been most probably proposed after breast cancer surgery mainly because of estrogen receptor ER negativity Therefore no overtreatment with anthracyclines will occur in this group of patients Pathological complete response pCR to epirubicin will be correlated with the topo II a gene and protein status The study has two biological hypotheses one for the subgroup of patients with ER negativeHER-2 amplified tumors the other one for the subgroup of patients with ER negativeHER-2 non amplified tumors
1 st hypothesis Patients with ER negativeHER-2 amplified tumors In this subgroup of patients topo II a gene will be amplified in about 40 of cases We hypothesize that in topo II a amplified tumors a three-fold increase in pCR rate will be observed as opposed to the pCR rate in tumors with topo II a normal or deleted gene
2 nd hypothesis Patients with ER negativeHER-2 non amplified tumors In this subset of patients almost no topo II a gene aberrations will be found based on previous data discussed above However recent data reported by C Sotiriou et al using cDNA microarrays suggest that in this subset of ER-negative HER-2 negative tumors also defined as the basal-like subset two distinct subgroups can be identified ie basal-like 1 and 2 While basal-like 1 tumors show a high proliferation rate and high levels of topo II a RNA basal-like 2 tumors have a moderate-low proliferation rate and normal levels of topo II a RNA We hypothesize that the topo II a RNA overexpression in basal-like 1 tumors is not related to topo II a gene amplification because no concomitant HER-2 gene amplification is reported in this subset of tumors The second study hypothesis is that in ER negativeHER-2 non amplified tumors with topo II a protein overexpression a 25 fold increase in pCR rate will be observed as opposed to the pCR rate in tumors with low topo II a protein content
A tumor sample drawn at the time of pre-treatment biopsy will be frozen and used to perform oligonucleotide based microarrays Affymetrix This technique allows the evaluation of thousands of genes and ultimately provides us with the tumor genetic profile Homogeneous genetic profiles genetic clusters that might be identified will be correlated with the efficacy of single-agent epirubicin This correlation will allow us to address the secondary end-point of this study which is the identification of other genes or eventually a genetic profile playing a role in the determination of sensitivity to anthracyclines Among the genes that could interfere with sensitivity to anthracyclines p-53 seems to deserve special attention Indeed in-vitro data suggest that at least some p-53 mutated tumors are poorly sensitive to anthracyclines primarily because anthracycline-induced apoptosis is prevented Interestingly p-53 mutated tumors display frequently HER-2 gene amplification and therefore topo II a gene amplification 23 Accordingly p-53 mutations could hamper response to anthracyclines even in tumors carrying topo II a gene amplification This hypothesis will also be explored in the present study because p-53 mutations will be evaluated by DNA sequencing and the efficacy of epirubicin in topo II a amplified and non-amplified tumors will be correlated with p-53 status
Additionally patients with inflammatory breast cancer will be treated with dense administration of epirubicin 100 mgm22 weeks We keep the same drug as for early breast cancer but we use a slightly more aggressive regimen with a higher dose-density The feasibility of the administration of epirubicin 100 mgm2 every two weeks with granulocyte-growth factor support has been shown in the neoadjuvant metastatic and adjuvant settings with acceptable toxicity This neoadjuvant epirubicin regimen may be completed by adjuvant chemotherapy such as taxane-based regimens since the sequential approach anthracyclines and taxanes has been suggested superior to anthracyclines regimen in LABC
Moreover our group has analyzed the predictive value of topo II a in a population of node-positive breast cancer patients randomly treated either with anthracyclines or with CMF Belgian cooperative trial In a first study topo II a was evaluated by immunohistochemistry which allows the detection of topo II a protein expression The results of this study suggested that patients deriving the highest benefit from anthracyclines were those in which topo II a protein is immunostained in more than 10 of tumor cells The main findings of this study should be seen as hypothesis-generating because of the limited number of patients evaluated about fifty in each study arm and because topo II a protein levels depend on gene amplification as well as on tumor proliferation rate Therefore topo II a protein expression does not necessarily reflect topo II a gene status
The second study run by our group was based on the same series of patients evaluated in the first study but this time both HER-2 and topo II a genes were evaluated by fluorescence in-situ hybridization FISH which allows the detection of gene aberrations The main findings of the second study were quite consistent with the pre-clinical data suggesting that only HER-2 amplifiedtopo II a amplified tumours show great sensitivity to anthracyclines while the efficacy of these same agents in HER-2 amplifiedtopo II a non-amplified tumors is comparable to the efficacy of other drugs or regimens like CMF
Nevertheless although the results reported in this study bring some additional support to the hypothesis of topo II a as a marker predicting the efficacy of anthracyclines no definitive conclusions can be drawn because of the fairly limited number of patients evaluated and the retrospective nature of the analyses
The present study protocol Supported by in-vitro and preliminary in-vivo data briefly summarized above this study is designed to test prospectively the value of topo II alpha gene amplification and protein overexpression in predicting the efficacy of anthracyclines To our knowledge this is the only prospective trial worldwide which is attempting to prospectively clarify the predictive value of this interesting biological marker This study could have important practical implications in the daily clinical management of early breast cancer patients because if the trial confirms that topo II a gene amplification andor protein overexpression are associated with high efficacy of anthracyclines while topo II a normaldeleted gene and low protein content are associated with modest efficacy an important step forward in the direction of anthracycline tailoring would be accomplished
The practical advantage of this approach would be to use anthracyclines primarily in patients who are supposed to derive the largest benefit thus sparing the long-term anthracycline-related toxicity ie secondary acute myeloid leukemia cardiac dysfunction and amenorrheasterility in case of fertile women to those patients for whom no significant gain in antitumor activity is anticipated
To reach this ambitious aim early breast cancer patients with tumors of at least 2 cm defined by breast ultrasound will be evaluated for topo II a gene and protein expression For this purpose a pre-treatment biopsy tru-cut will be performed and topo II a gene will be evaluated on fixed samples by FISH The use of a triple probe will allow the concomitant evaluation of the HER-2 gene status Topo II a protein will be evaluated by immunohistochemistry IHC Afterwards all patients independently of the topo II a gene and protein status will be treated with single-agent epirubicin Eligibility criteria will allow the participation of patients for whom the use of an anthracycline-based adjuvant therapy would have been most probably proposed after breast cancer surgery mainly because of estrogen receptor ER negativity Therefore no overtreatment with anthracyclines will occur in this group of patients Pathological complete response pCR to epirubicin will be correlated with the topo II a gene and protein status The study has two biological hypotheses one for the subgroup of patients with ER negativeHER-2 amplified tumors the other one for the subgroup of patients with ER negativeHER-2 non amplified tumors
1 st hypothesis Patients with ER negativeHER-2 amplified tumors In this subgroup of patients topo II a gene will be amplified in about 40 of cases We hypothesize that in topo II a amplified tumors a three-fold increase in pCR rate will be observed as opposed to the pCR rate in tumors with topo II a normal or deleted gene
2 nd hypothesis Patients with ER negativeHER-2 non amplified tumors In this subset of patients almost no topo II a gene aberrations will be found based on previous data discussed above However recent data reported by C Sotiriou et al using cDNA microarrays suggest that in this subset of ER-negative HER-2 negative tumors also defined as the basal-like subset two distinct subgroups can be identified ie basal-like 1 and 2 While basal-like 1 tumors show a high proliferation rate and high levels of topo II a RNA basal-like 2 tumors have a moderate-low proliferation rate and normal levels of topo II a RNA We hypothesize that the topo II a RNA overexpression in basal-like 1 tumors is not related to topo II a gene amplification because no concomitant HER-2 gene amplification is reported in this subset of tumors The second study hypothesis is that in ER negativeHER-2 non amplified tumors with topo II a protein overexpression a 25 fold increase in pCR rate will be observed as opposed to the pCR rate in tumors with low topo II a protein content
A tumor sample drawn at the time of pre-treatment biopsy will be frozen and used to perform oligonucleotide based microarrays Affymetrix This technique allows the evaluation of thousands of genes and ultimately provides us with the tumor genetic profile Homogeneous genetic profiles genetic clusters that might be identified will be correlated with the efficacy of single-agent epirubicin This correlation will allow us to address the secondary end-point of this study which is the identification of other genes or eventually a genetic profile playing a role in the determination of sensitivity to anthracyclines Among the genes that could interfere with sensitivity to anthracyclines p-53 seems to deserve special attention Indeed in-vitro data suggest that at least some p-53 mutated tumors are poorly sensitive to anthracyclines primarily because anthracycline-induced apoptosis is prevented Interestingly p-53 mutated tumors display frequently HER-2 gene amplification and therefore topo II a gene amplification 23 Accordingly p-53 mutations could hamper response to anthracyclines even in tumors carrying topo II a gene amplification This hypothesis will also be explored in the present study because p-53 mutations will be evaluated by DNA sequencing and the efficacy of epirubicin in topo II a amplified and non-amplified tumors will be correlated with p-53 status
Additionally patients with inflammatory breast cancer will be treated with dense administration of epirubicin 100 mgm22 weeks We keep the same drug as for early breast cancer but we use a slightly more aggressive regimen with a higher dose-density The feasibility of the administration of epirubicin 100 mgm2 every two weeks with granulocyte-growth factor support has been shown in the neoadjuvant metastatic and adjuvant settings with acceptable toxicity This neoadjuvant epirubicin regimen may be completed by adjuvant chemotherapy such as taxane-based regimens since the sequential approach anthracyclines and taxanes has been suggested superior to anthracyclines regimen in LABC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| CE1141 | None | None | None |