Ignite Creation Date:
2024-05-05 @ 11:59 AM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00206466
Status:
COMPLETED
Last Update Posted:
2012-01-25
First Post:
2005-09-13
Brief Title:
Biologic Correlative TaxotereAC
Sponsor:
Baylor Breast Care Center
Organization:
Baylor Breast Care Center
Study Overview
Official Title:
A Randomized Multicenter Trial of Neoadjuvant Taxotere and AdriamycinCytoxanAC A Biologic Correlative Study
Status:
COMPLETED
Status Verified Date:
2012-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TAXAC
Brief Summary:
We are asking you to take part in a research study of biomarkers characteristics or traits of the genes inside cancer cells We want to learn if these biomarkers could help us learn how well your breast cancer may respond improve to chemotherapy drugs to treat cancer
Detailed Description:
Breast cancer and systemic chemotherapy Systemic chemotherapy for operable breast cancer significantly decreases the risk of relapse and death However it is not possible to identify those patients at the outset who are likely to respond to adjuvant treatment and which type of treatment should be used Adjuvant treatment given before surgery neoadjuvant therapy has a number of advantages in breast cancer including a reduction in the requirement for mastectomy Access to the primary tumor during early treatment allows for in vivo testing for predictive markers obtained by core biopsies that occur with successful treatment
Predictive markers in breast cancer Prognostic factors like tumor size and nodal involvement are important indicators for breast cancer survival but have not been shown to be predictive of sensitivity to chemotherapy With endocrine therapy the prime example of a predictive marker is estrogen receptor ER expression which predicts for response to tamoxifen and other endocrine treatments However predictive markers for chemotherapy are not established Overexpression of c-erbB-2 might be associated with decreased response to CMF and increased response to anthracycline-based treatment but these observations are still contentious Expression of topoisomerase II may also reflect responsiveness to anthracycline chemotherapy Recently some emerging data also suggest that c-erbB2 may be a marker of taxane sensitivity As such we lack predictive biomarkers that could give early information on how effective chemotherapy is and whether additional treatment might be beneficial A test for chemotherapy sensitivity equivalent to ER in predicting response to endocrine therapy would greatly facilitate treatment decisions so that in an ideal scenario the treatment of each individual patient could be based on specific features of her disease
Neoadjuvant chemotherapy Preoperative chemotherapy for large tumors 3cm or inoperable breast cancer is well established and is the standard of care for locally advanced breast cancer Data from large series of patients have demonstrated that preoperative neoadjuvant chemotherapy leads to significant reduction of tumor size downstaging and improves both the rate and the cosmetic results of breast-conserving surgery A recent large randomized trial involving 1523 patients compared preoperative and postoperative chemotherapy NSABP B-18 Although results of this study have shown no difference in disease-free survival and survival in women on preoperative or postoperative doxorubicin and cyclophosphamide chemotherapy significant downstaging of tumors was achieved so that more patients who received preoperative therapy were able to undergo breast-conserving surgery The rate of breast conservation in NSABP B-18 was 85 in patients with tumors greater than 3 cm with less than 5 of patients reported to have progressive disease while receiving neoadjuvant chemotherapy
cDNA arrays High-Throughput Quantitative Profiling of Gene Expression With the advent of high-throughput quantitation of gene expression and cDNA technology it is now possible to study expression of many genes simultaneously to characterize expression patterns in different breast cancers that may distinguish molecular phenotypes associated with clinical response to a treatment In a recent report a molecular classification of leukemia was demonstrated Bone marrow aspirates taken from 38 patients with acute leukemia were evaluated for expression of 6817 human genes The 50 best discriminating genes were used to create a predictive index that was then applied to new samples and was found to accurately assign them as AML or ALL
Preliminary data for differential patterns of gene expression in responders vs non-responders of Taxotere chemotherapy We conducted a pilot study to investigate gene expression patterns on core biopsies of human breast cancers in responders and non-responders to Taxotere chemotherapy
RNA was isolated from core biopsies of primary breast cancers taken from women before initiation of Taxotere chemotherapy Clinical response was assessed after 12 weeks of treatment We compared patterns of gene expression statistically in order to identify genes differentially expressed between responders and non-responders to this single chemotherapeutic agent
Overall these genes efficiently cluster tumors into 3 groups CR PR and NR We have selected 2337 genes from these data for further analysis As expected the majority of these genes show heterogeneous expression patterns independent of treatment response but six large gene clusters approximately 180 genes appear to predict likelihood of response to Taxotere therapy Consistent with an apoptosis-induction mode of action for taxanes responsive tumors appear to have higher expression of stress-related proteins such as mitochondrial proteins involved in apoptosis cytochromes proteasome subunits and higher levels of motility-related microfilament proteins actin myosin and tropomyosin Non-responders patterns are more complex but show elevated levels of some microtubule proteins presumed to be targets of Taxotere therapy tubulins tubulin-interacting proteins and elevated levels of inflammatory-response genes Surprisingly non-responders also showed elevated proliferation KI67 and oncogene ABL1 MYC and JUNB expression levels This molecular portrait of Taxotere resistance differs from the expected profiles of general chemoresistance Quantitative RT-PCR and immunohistochemistry studies to confirm these differential gene patterns of expression are in progress for all 40 patients
Predictive markers in breast cancer Prognostic factors like tumor size and nodal involvement are important indicators for breast cancer survival but have not been shown to be predictive of sensitivity to chemotherapy With endocrine therapy the prime example of a predictive marker is estrogen receptor ER expression which predicts for response to tamoxifen and other endocrine treatments However predictive markers for chemotherapy are not established Overexpression of c-erbB-2 might be associated with decreased response to CMF and increased response to anthracycline-based treatment but these observations are still contentious Expression of topoisomerase II may also reflect responsiveness to anthracycline chemotherapy Recently some emerging data also suggest that c-erbB2 may be a marker of taxane sensitivity As such we lack predictive biomarkers that could give early information on how effective chemotherapy is and whether additional treatment might be beneficial A test for chemotherapy sensitivity equivalent to ER in predicting response to endocrine therapy would greatly facilitate treatment decisions so that in an ideal scenario the treatment of each individual patient could be based on specific features of her disease
Neoadjuvant chemotherapy Preoperative chemotherapy for large tumors 3cm or inoperable breast cancer is well established and is the standard of care for locally advanced breast cancer Data from large series of patients have demonstrated that preoperative neoadjuvant chemotherapy leads to significant reduction of tumor size downstaging and improves both the rate and the cosmetic results of breast-conserving surgery A recent large randomized trial involving 1523 patients compared preoperative and postoperative chemotherapy NSABP B-18 Although results of this study have shown no difference in disease-free survival and survival in women on preoperative or postoperative doxorubicin and cyclophosphamide chemotherapy significant downstaging of tumors was achieved so that more patients who received preoperative therapy were able to undergo breast-conserving surgery The rate of breast conservation in NSABP B-18 was 85 in patients with tumors greater than 3 cm with less than 5 of patients reported to have progressive disease while receiving neoadjuvant chemotherapy
cDNA arrays High-Throughput Quantitative Profiling of Gene Expression With the advent of high-throughput quantitation of gene expression and cDNA technology it is now possible to study expression of many genes simultaneously to characterize expression patterns in different breast cancers that may distinguish molecular phenotypes associated with clinical response to a treatment In a recent report a molecular classification of leukemia was demonstrated Bone marrow aspirates taken from 38 patients with acute leukemia were evaluated for expression of 6817 human genes The 50 best discriminating genes were used to create a predictive index that was then applied to new samples and was found to accurately assign them as AML or ALL
Preliminary data for differential patterns of gene expression in responders vs non-responders of Taxotere chemotherapy We conducted a pilot study to investigate gene expression patterns on core biopsies of human breast cancers in responders and non-responders to Taxotere chemotherapy
RNA was isolated from core biopsies of primary breast cancers taken from women before initiation of Taxotere chemotherapy Clinical response was assessed after 12 weeks of treatment We compared patterns of gene expression statistically in order to identify genes differentially expressed between responders and non-responders to this single chemotherapeutic agent
Overall these genes efficiently cluster tumors into 3 groups CR PR and NR We have selected 2337 genes from these data for further analysis As expected the majority of these genes show heterogeneous expression patterns independent of treatment response but six large gene clusters approximately 180 genes appear to predict likelihood of response to Taxotere therapy Consistent with an apoptosis-induction mode of action for taxanes responsive tumors appear to have higher expression of stress-related proteins such as mitochondrial proteins involved in apoptosis cytochromes proteasome subunits and higher levels of motility-related microfilament proteins actin myosin and tropomyosin Non-responders patterns are more complex but show elevated levels of some microtubule proteins presumed to be targets of Taxotere therapy tubulins tubulin-interacting proteins and elevated levels of inflammatory-response genes Surprisingly non-responders also showed elevated proliferation KI67 and oncogene ABL1 MYC and JUNB expression levels This molecular portrait of Taxotere resistance differs from the expected profiles of general chemoresistance Quantitative RT-PCR and immunohistochemistry studies to confirm these differential gene patterns of expression are in progress for all 40 patients
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