Breast Cancer, Stage IV Breast Cancer
Conditions
Keywords
estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, stage IV breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate may fight cancer by blocking the use of estrogen by tumor cells. PURPOSE: This phase II trial is studying how well tamoxifen citrate works in patients with metastatic or recurrent breast cancer.
Detailed description
OBJECTIVES: Primary * To correlate CYP2D6 (Cytochrome P450 2D6) score (0 vs 1-2) and progression-free survival (PFS) Secondary * To correlate CYP2D6 score (0 vs 1 vs 2) and PFS * To correlate CYP2D6 score (0 vs 1-2) and the proportion of these patients who are progression-free at 6 months. * To correlate endoxifen concentration with response * To correlate CYP2D6 with response * To correlate the presence of candidate estrogen receptor (ESR) 1 and 2 variant alleles, UDP-glucuronosyltransferases (UGT) 7, sulfotransferases (SULT) 1A1, other candidate genes and biomarkers to PFS and other tamoxifen related outcomes OUTLINE: This is a multicenter study. Patients receive oral tamoxifen citrate once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities. Blood, plasma, and tissue samples are collected periodically for laboratory studies. After completion of study therapy, patients are followed up every 3-6 months for 5 years.
Interventions
DRUGtamoxifen
PO
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed adenocarcinoma of the breast * Stage III (locally advanced), metastatic, or recurrent disease * Deemed not resectable * Estrogen-receptor and/or progesterone-receptor positive disease * Receptor status is based on most recent results * Measurable or non-measurable disease * ECOG performance status 0-2 * History of central nervous system (CNS) metastasis allowed provided it has been treated (surgery, radiotherapy, or radiosurgery) within the past 4 weeks and does not require medications to control symptoms * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases present) * Negative pregnancy test * Fertile patients must use effective nonhormonal contraception * Disease-free of prior invasive malignancies for ≥ 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix * Prior chemotherapy, trastuzumab, or bevacizumab in the adjuvant setting allowed provided it has been completed ≥ 4 weeks before study therapy; other prior non-hormonal investigational agents in the adjuvant setting must have been completed at least 4 weeks prior to study registration and should be discussed with the study PI * Prior tamoxifen as adjuvant treatment is allowed as long as the patient did not have disease relapse or progression while on adjuvant tamoxifen or within 4 weeks of last dose * Treatment in the advanced setting must have been completed at least 2 weeks prior to study initiation * Prior aromatase inhibitors (e.g., anastrozole, letrozole, exemestane, aminoglutethamide) are allowed in the adjuvant or metastatic setting * At least 2 weeks since prior and no concurrent medications that are strong to moderate inhibitors of CYP2D6 and may alter tamoxifen citrate metabolism including, but not limited to, any of the following: * Paroxetine (Paxil) * Fluoxetine (Prozac) * Bupropion (Wellbutrin) * Quinidine (Cardioquin) * Concurrent radiotherapy to painful sites of bone disease or areas of impending fractures allowed provided the following criteria are met: * Radiotherapy was initiated before study entry * Sites of measurable or non-measurable disease are outside the radiotherapy port * Recovered from prior radiotherapy
Exclusion criteria
* Pregnant or nursing * Concurrent chemotherapy * Leptomeningeal disease * Non-protocol concurrent hormonal therapy * Medical or psychiatric conditions that would interfere with protocol compliance, the ability to provide informed consent, assessment of response, or anticipated toxicities * Prior tamoxifen for advanced disease * More than 2 lines of non-hormonal treatment in the locally advanced or metastatic setting, including trastuzumab (Herceptin), bevacizumab, or other biologics * Starting bisphosphonate therapy while receiving treatment on this study * Patients who have begun receiving bisphosphonate therapy prior to registration may continue at the same intervals used prior to study registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival by CYP2D6 Status in 2 Categories | Assessed every 3 months for 2 years, then every 6 months up to 5 years | Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival by CYP2D6 Status in 3 Categories | Assessed every 3 months for 2 years, then every 6 months up to 5 years | Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Proportion of Patients Progression-free at 6 Months | Assessed every 3 months for 6 months | Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Proportion of Patients With Response | Assessed every 3 months for 2 years, then every 6 months up to 5 years | Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Endoxifen Concentration by Response | Endoxifen was assessed at cycle 3; response was assessed every 3 months for 2 years, then every 6 months up to 5 years | Endoxifen (ng/ml) was assessed at cycle 3. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Progression-free Survival From 3 Months Post Registration | Assessed every 3 months for 2 years, then every 6 months up to 5 years | This is a landmark progression-free survival analysis at 3 months post registration. Only patients who were progression-free and alive at 3 months were included. Progression-free survival in this analysis is defined as the time from 3 months post registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
Countries
Canada, Peru, United States
Participant flow
Recruitment details
The study was activated on September 21, 2010, accrued its first patient on January 7, 2011, and closed on October 22, 2015 for a total of 124 patients enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Tamoxifen Patients receive oral tamoxifen citrate at 20 mg once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities. | 113 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Alternative therapy | 9 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 77 |
| Overall Study | Ineligible | 9 |
| Overall Study | Ineligible and never start treatment | 2 |
| Overall Study | No documentation that patient went off treatment | 4 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Tamoxifen |
|---|---|
| Age, Continuous | 62 years |
| CYP2D6 phenotype Intermediate metabolizer | 27 Participants |
| CYP2D6 phenotype Missing | 28 Participants |
| CYP2D6 phenotype Normal metabolizer | 50 Participants |
| CYP2D6 phenotype Poor metabolizer | 2 Participants |
| CYP2D6 phenotype Ultra-rapid metabolizer | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 97 Participants |
| Sex: Female, Male Female | 111 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 69 / 124 |
| other Total, other adverse events | 18 / 122 |
| serious Total, serious adverse events | 30 / 122 |
Outcome results
Primary
Progression-free Survival by CYP2D6 Status in 2 Categories
Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 2 years, then every 6 months up to 5 years
Population: Eligible and treated patients who had a sample from baseline evaluable for CYP2D6 phenotype
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CYP2D6 - PM | Progression-free Survival by CYP2D6 Status in 2 Categories | 12.9 months |
| CYP2D6 - (IM+NM+UM) | Progression-free Survival by CYP2D6 Status in 2 Categories | 6.9 months |
Secondary
Endoxifen Concentration by Response
Endoxifen (ng/ml) was assessed at cycle 3. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Endoxifen was assessed at cycle 3; response was assessed every 3 months for 2 years, then every 6 months up to 5 years
Population: Eligible and treated patients who had a sample at cycle 3 for endoxifen concentration evaluation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CYP2D6 - PM | Endoxifen Concentration by Response | 17.5 ng/ml |
| CYP2D6 - (IM+NM+UM) | Endoxifen Concentration by Response | 17.2 ng/ml |
Secondary
Progression-free Survival by CYP2D6 Status in 3 Categories
Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 2 years, then every 6 months up to 5 years
Population: Eligible and treated patients who had a sample from baseline evaluable for CYP2D6 phenotype
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CYP2D6 - PM | Progression-free Survival by CYP2D6 Status in 3 Categories | 12.9 months |
| CYP2D6 - (IM+NM+UM) | Progression-free Survival by CYP2D6 Status in 3 Categories | 4.8 months |
| CYP2D6 - NM+UM | Progression-free Survival by CYP2D6 Status in 3 Categories | 7.4 months |
Secondary
Progression-free Survival From 3 Months Post Registration
This is a landmark progression-free survival analysis at 3 months post registration. Only patients who were progression-free and alive at 3 months were included. Progression-free survival in this analysis is defined as the time from 3 months post registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 2 years, then every 6 months up to 5 years
Population: Eligible and treated patients who had endoxifen level assessed at 3 months and were progression-free and alive at 3 months from registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CYP2D6 - PM | Progression-free Survival From 3 Months Post Registration | 13.8 months |
| CYP2D6 - (IM+NM+UM) | Progression-free Survival From 3 Months Post Registration | 11.1 months |
Secondary
Proportion of Patients Progression-free at 6 Months
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 6 months
Population: Eligible and treated patients who had a sample from baseline evaluable for CYP2D6 phenotype
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CYP2D6 - PM | Proportion of Patients Progression-free at 6 Months | 1.0 proportion of participants |
| CYP2D6 - (IM+NM+UM) | Proportion of Patients Progression-free at 6 Months | 0.50 proportion of participants |
Secondary
Proportion of Patients With Response
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Assessed every 3 months for 2 years, then every 6 months up to 5 years
Population: Eligible and treated patients who had a sample from baseline evaluable for CYP2D6 phenotype
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CYP2D6 - PM | Proportion of Patients With Response | 0 proportion of participants |
| CYP2D6 - (IM+NM+UM) | Proportion of Patients With Response | 0.13 proportion of participants |