Breast Cancer, Menopausal Symptoms
Conditions
Keywords
menopausal symptoms, recurrent breast cancer, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, ductal breast carcinoma in situ, breast cancer in situ
Brief summary
RATIONALE: Studying samples of blood from patients with cancer in the laboratory may help doctors learn more about differences in DNA and predict how well patients will respond to treatment and plan better treatment. PURPOSE: This clinical trial is studying blood samples from women with breast cancer or ductal carcinoma in situ who are receiving tamoxifen.
Detailed description
OBJECTIVES: Primary * To evaluate the change in endoxifen levels after an increase in tamoxifen citrate dose from 20 mg to 40 mg in women with breast cancer or ductal breast carcinoma in situ with intermediate-metabolizing CYP2D6 genotypes. Secondary * To evaluate the tolerability of increasing the dose of tamoxifen citrate from 20 to 40 mg per day in these patients. * To assess the feasibility of obtaining pharmacogenomic information from patients in the clinical setting and using it to guide changes in therapy. * To examine CYP2D6 allele frequencies and endoxifen levels among African-American women taking tamoxifen citrate. * To evaluate the change in plasma endoxifen levels after an increase in the tamoxifen citrate dose from 20 mg to 40 mg daily in patients with poor-metabolizing genotypes. * To study patient understanding of pharmacogenomics and obstacles to participation in clinical trials based upon germline DNA. OUTLINE: This is a multicenter study. Blood samples are collected at baseline to determine CYP2D6 genotype and tamoxifen citrate metabolic status: poor-metabolizing (PM), intermediate-metabolizing (IM), or extensive-metabolizing (EM) alleles. Samples are also analyzed for plasma levels of endoxifen and N-desmethyltamoxifen and for endoxifen/N-desmethyltamoxifen ratio. Patients found to be IM or PM are notified to increased tamoxifen citrate to 40 mg/day for 4 months (in the absence of unacceptable toxicity) with repeat endoxifen and N-desmethyltamoxifen levels (and the ratio) at the end of this time. All patients complete Quality Of Life (QOL) and Menopausal Symptoms Scale (MSS) questionnaires at baseline and after 4 months of treatment. Toxicities are assessed at the end of 4 months. Patients undergo repeat questionnaire assessment of their understanding of the use of pharmacogenomics in clinical decision-making. Some patients also undergo a 30-minute, baseline interview regarding attitudes and experience towards participation in a pharmacogenomics study. Patients who choose to be informed of the results of their genotyping are contacted by letter, along with their physicians, and offered genetic counseling to discuss the significance of these results. After completion of study therapy, patients are followed at 3-6 months, including toxicity assessment and QOL and MSS questionnaires.
Interventions
DRUGtamoxifen citrate
Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis.
GENETICgene expression analysis
Genetic analysis of blood sample.
OTHERpharmacogenomic studies
Genetic analysis of blood sample.
OTHERquestionnaire administration
Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months
PROCEDUREquality-of-life assessment
Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.
Sponsors
National Cancer Institute (NCI)
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: Histologically confirmed invasive carcinoma of the breast or ductal breast carcinoma in situ Has been receiving tamoxifen citrate at a dose of 20 mg/day for at least 4 months either for the treatment of invasive or non-invasive carcinoma of the breast or for breast cancer recurrence prevention * Expected duration of tamoxifen citrate treatment at least 6 months Hormone receptor status not specified Concurrent participation in non-treatment studies allowed provided it will not interfere with participation in this study Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 6 months Absolute Neutrophil Count (ANC) ≥ 1.0 x 10\^9/L Platelet count ≥ 100 x 10\^9/L Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal (ULN) Total bilirubin ≤ 2.5 times ULN Creatinine clearance ≥ 50 mL/min Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * No limitations to number of prior therapies * No limitations for prior radiotherapy * More than 14 days since prior and no other concurrent investigational agent Exclusion: Not pregnant or nursing No active, serious infection or medical or psychiatric illness likely to preclude study participation No psychiatric conditions that would preclude study compliance or informed consent No history of venous thromboembolism, transient ischemic attack, or cerebral vascular accident No history of allergic reaction to tamoxifen citrate or any of its reagents No concurrent coumadin No concurrent medications known to inhibit CYP2D6, including any of the following: * Amiodarone * Haloperidol * Indinavir * Ritonavir * Quinidine No concurrent selective serotonin reuptake inhibitors, except the following: * Venlafaxine * Citalopram
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | 4 months | Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Approximately ten months from registration to last follow-up | The doubling of tamoxifen dose is defined as unacceptable (i.e., not tolerable) if the prevalence of Pulmonary embolism (PE), Deep vein thrombosis (DVT), stroke, or endometrial cancer, either individually or in any combination, is greater than 2%. |
| Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy | Baseline and 4 months after dose increase | If the key active tamoxifen metabolite, endoxifen, could be significantly increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism (by increasing tamoxifen dosing based on CYP2D6 genotype), then the study would be deemed feasible and the accrual expanded. |
| CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | baseline | Mean endoxifen levels by CYP2D6 genotype among African Americans. Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline.The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM. |
| Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes | Baseline and 4 months after dose increase | The intrapatient change in median endoxifen levels were calculated between baseline and 4 months after the increase in dose of Tamoxifen from 20mg/day to 40 mg/day |
| Patient Understanding of Pharmacogenomics | baseline | To examine patients' beliefs about how hypothetical genotype information would affect their perceived recurrence risk and benefits of tamoxifen therapy, participants were given experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, participants gave their perceived recurrence risk (RR; 0-100%) |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from breast cancer patients at Lineberger Comprehensive Cancer Center who had received tamoxifen for at least 4 months.
Pre-assignment details
One patient was a screen failure
Participants by arm
| Arm | Count |
|---|---|
| Extensive and Ultra-rapid Metabolizers Those with the highest endoxifen concentrations as measured at baseline. | 161 |
| Intermediate and Poor Metabolizers Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day. | 319 |
| Total | 480 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | No CYP2D6 genotyping | 9 |
| Overall Study | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | Intermediate and Poor Metabolizers | Total | Extensive and Ultra-rapid Metabolizers |
|---|---|---|---|
| Age, Continuous Median | 50 years | 50 years | 51 years |
| Duration of Tamoxifen treatment (years) | 0.98 years | 0.93 years | 0.88 years |
| Menopausal status Post- | 165 Participants | 256 Participants | 91 Participants |
| Menopausal status Pre/peri- | 154 Participants | 224 Participants | 70 Participants |
| Prior chemotherapy No | 150 Participants | 219 Participants | 69 Participants |
| Prior chemotherapy Yes | 169 Participants | 261 Participants | 92 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 74 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) White | 250 Participants | 390 Participants | 140 Participants |
| Region of Enrollment United States | 319 Participants | 480 Participants | 161 Participants |
| Sex: Female, Male Female | 319 Participants | 480 Participants | 161 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tamoxifen indication DCIS | 49 Participants | 66 Participants | 17 Participants |
| Tamoxifen indication Invasive Disease | 263 Participants | 407 Participants | 144 Participants |
| Tamoxifen indication Other | 6 Participants | 6 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 161 | 0 / 290 | 0 / 29 |
| other Total, other adverse events | 149 / 161 | 274 / 290 | 26 / 29 |
| serious Total, serious adverse events | 0 / 161 | 3 / 290 | 0 / 29 |
Outcome results
Primary
Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes
Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.
Time frame: 4 months
Population: Baseline measurements are reported on all 353 subjects, while the 4 month levels are reported only for patients who completed 4 months of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ultra-rapid Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | Baseline endoxifen concentration | 8.4 ng/mL | Standard Deviation 4.59 |
| Ultra-rapid Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | 4-Month endoxifen concentration | 15.35 ng/mL | Standard Deviation 5.48 |
| Extensive Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | 4-Month endoxifen concentration | 9.30 ng/mL | Standard Deviation 5.03 |
| Extensive Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | Baseline endoxifen concentration | 10.00 ng/mL | Standard Deviation 6 |
| Intermediate Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | Baseline endoxifen concentration | 7.10 ng/mL | Standard Deviation 4.77 |
| Intermediate Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | 4-Month endoxifen concentration | 10.74 ng/mL | Standard Deviation 7.36 |
| Poor Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | Baseline endoxifen concentration | 3.42 ng/mL | Standard Deviation 2.75 |
| Poor Metabolizers | Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | 4-Month endoxifen concentration | 5.52 ng/mL | Standard Deviation 2.57 |
Secondary
Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy
If the key active tamoxifen metabolite, endoxifen, could be significantly increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism (by increasing tamoxifen dosing based on CYP2D6 genotype), then the study would be deemed feasible and the accrual expanded.
Time frame: Baseline and 4 months after dose increase
Population: This was based on the initial 119 subjects enrolled (based on initial sample size of 100) and of those, the 89 that completed 4 months of tamoxifen therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ultra-rapid Metabolizers | Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy | -1.5 ng/mL |
| Extensive Metabolizers | Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy | 7.6 ng/mL |
| Intermediate Metabolizers | Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy | 6.1 ng/mL |
Secondary
Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes
The intrapatient change in median endoxifen levels were calculated between baseline and 4 months after the increase in dose of Tamoxifen from 20mg/day to 40 mg/day
Time frame: Baseline and 4 months after dose increase
Population: Analysis limited to only those subjects with the Poor Metabolizing (PM) genotype who were evaluable at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ultra-rapid Metabolizers | Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes | 6.1 ng/mL |
Secondary
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate
Mean endoxifen levels by CYP2D6 genotype among African Americans. Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline.The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.
Time frame: baseline
Population: Only participants who self-identified as African American were included in this analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ultra-rapid Metabolizers | CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | UM | 14.58 ng/ml |
| Ultra-rapid Metabolizers | CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | EM | 9.69 ng/ml |
| Ultra-rapid Metabolizers | CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | IM | 7.09 ng/ml |
| Ultra-rapid Metabolizers | CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | PM | 0.8 ng/ml |
Secondary
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer
The doubling of tamoxifen dose is defined as unacceptable (i.e., not tolerable) if the prevalence of Pulmonary embolism (PE), Deep vein thrombosis (DVT), stroke, or endometrial cancer, either individually or in any combination, is greater than 2%.
Time frame: Approximately ten months from registration to last follow-up
Population: Incidence of unacceptable adverse events among all patients who completed study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ultra-rapid Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Deep vein thrombosis (DVT) | 0 Participants |
| Ultra-rapid Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Pulmonary embolism (PE) | 0 Participants |
| Ultra-rapid Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Stroke | 0 Participants |
| Ultra-rapid Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Endometrial cancer | 0 Participants |
| Extensive Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Endometrial cancer | 0 Participants |
| Extensive Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Stroke | 0 Participants |
| Extensive Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Pulmonary embolism (PE) | 0 Participants |
| Extensive Metabolizers | Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | Deep vein thrombosis (DVT) | 0 Participants |
Secondary
Patient Understanding of Pharmacogenomics
To examine patients' beliefs about how hypothetical genotype information would affect their perceived recurrence risk and benefits of tamoxifen therapy, participants were given experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, participants gave their perceived recurrence risk (RR; 0-100%)
Time frame: baseline
Population: Of 377 patients who were eligible to complete the survey, 320 patients completed the survey and 57 returned incomplete surveys
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR -No tamoxifen/EM | 47 percent chance of recurrence |
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR -No tamoxifen/iM | 48 percent chance of recurrence |
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR -No tamoxifen/PM | 53 percent chance of recurrence |
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR - tamoxifen/EM | 22 percent chance of recurrence |
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR -tamoxifen/IM | 30 percent chance of recurrence |
| Ultra-rapid Metabolizers | Patient Understanding of Pharmacogenomics | Perceived RR -tamoxifen/PM | 40 percent chance of recurrence |