Trial Outcomes & Findings for Studying Blood Samples From Women With Breast Cancer or Ductal Carcinoma In Situ Who Are Receiving Tamoxifen (NCT NCT00764322)

Last Updated: 2017-08-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

501 participants

Primary outcome timeframe

4 months

Results posted on

2017-08-01

Participant Flow

Participants were recruited from breast cancer patients at Lineberger Comprehensive Cancer Center who had received tamoxifen for at least 4 months.

One patient was a screen failure

Participant milestones

Participant milestones
Measure	Patients Enrolled
Overall Study STARTED	500
Overall Study COMPLETED	480
Overall Study NOT COMPLETED	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Patients Enrolled
Overall Study Withdrawal by Subject	11
Overall Study No CYP2D6 genotyping	9

Baseline Characteristics

One patient could not be included because indication was not supplied.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Extensive and Ultra-rapid Metabolizers n=161 Participants Those with the highest endoxifen concentrations as measured at baseline.	Intermediate and Poor Metabolizers n=319 Participants Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Total n=480 Participants Total of all reporting groups
Age, Continuous Median	51 years n=161 Participants	50 years n=319 Participants	50 years n=480 Participants
Sex: Female, Male Female	161 Participants n=161 Participants	319 Participants n=319 Participants	480 Participants n=480 Participants
Sex: Female, Male Male	0 Participants n=161 Participants	0 Participants n=319 Participants	0 Participants n=480 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=161 Participants	0 Participants n=319 Participants	0 Participants n=480 Participants
Race (NIH/OMB) Asian	0 Participants n=161 Participants	0 Participants n=319 Participants	0 Participants n=480 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=161 Participants	0 Participants n=319 Participants	0 Participants n=480 Participants
Race (NIH/OMB) Black or African American	13 Participants n=161 Participants	61 Participants n=319 Participants	74 Participants n=480 Participants
Race (NIH/OMB) White	140 Participants n=161 Participants	250 Participants n=319 Participants	390 Participants n=480 Participants
Race (NIH/OMB) More than one race	0 Participants n=161 Participants	0 Participants n=319 Participants	0 Participants n=480 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=161 Participants	8 Participants n=319 Participants	16 Participants n=480 Participants
Region of Enrollment United States	161 Participants n=161 Participants	319 Participants n=319 Participants	480 Participants n=480 Participants
Menopausal status Pre/peri-	70 Participants n=161 Participants	154 Participants n=319 Participants	224 Participants n=480 Participants
Menopausal status Post-	91 Participants n=161 Participants	165 Participants n=319 Participants	256 Participants n=480 Participants
Duration of Tamoxifen treatment (years)	0.88 years n=161 Participants	0.98 years n=319 Participants	0.93 years n=480 Participants
Prior chemotherapy Yes	92 Participants n=161 Participants	169 Participants n=319 Participants	261 Participants n=480 Participants
Prior chemotherapy No	69 Participants n=161 Participants	150 Participants n=319 Participants	219 Participants n=480 Participants
Tamoxifen indication Invasive Disease	144 Participants n=161 Participants • One patient could not be included because indication was not supplied.	263 Participants n=318 Participants • One patient could not be included because indication was not supplied.	407 Participants n=479 Participants • One patient could not be included because indication was not supplied.
Tamoxifen indication DCIS	17 Participants n=161 Participants • One patient could not be included because indication was not supplied.	49 Participants n=318 Participants • One patient could not be included because indication was not supplied.	66 Participants n=479 Participants • One patient could not be included because indication was not supplied.
Tamoxifen indication Other	0 Participants n=161 Participants • One patient could not be included because indication was not supplied.	6 Participants n=318 Participants • One patient could not be included because indication was not supplied.	6 Participants n=479 Participants • One patient could not be included because indication was not supplied.

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=5 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers n=119 Participants Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers n=212 Participants Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers n=17 Participants Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
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	10.00 ng/mL Standard Deviation 6.00	7.10 ng/mL Standard Deviation 4.77	3.42 ng/mL Standard Deviation 2.75
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	9.30 ng/mL Standard Deviation 5.03	10.74 ng/mL Standard Deviation 7.36	5.52 ng/mL Standard Deviation 2.57

SECONDARY outcome

Timeframe: Approximately ten months from registration to last follow-up

Population: Incidence of unacceptable adverse events among all patients who completed study

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%.

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=161 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers n=319 Participants Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer Pulmonary embolism (PE)	0 Participants	0 Participants	—	—
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer Deep vein thrombosis (DVT)	0 Participants	0 Participants	—	—
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer Stroke	0 Participants	0 Participants	—	—
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer Endometrial cancer	0 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=29 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers n=51 Participants Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers n=9 Participants Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
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 Interval -28.0 to 11.2	7.6 ng/mL Interval -0.6 to 23.9	6.1 ng/mL Interval 2.6 to 12.5	—

SECONDARY outcome

Timeframe: baseline

Population: Only participants who self-identified as African American were included in this analysis

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.

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=52 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate UM	14.58 ng/ml Interval 14.58 to 14.58	—	—	—
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate EM	9.69 ng/ml Interval 1.08 to 21.98	—	—	—
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate IM	7.09 ng/ml Interval 1.07 to 20.89	—	—	—
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate PM	0.8 ng/ml Interval 0.8 to 0.8	—	—	—

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=11 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
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 Interval 2.6 to 12.5	—	—	—

SECONDARY outcome

Timeframe: baseline

Population: Of 377 patients who were eligible to complete the survey, 320 patients completed the survey and 57 returned incomplete surveys

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%)

Outcome measures

Outcome measures
Measure	Ultra-rapid Metabolizers n=320 Participants Those with the highest transformation of the CYP2D6 genotype to allelic activity	Extensive Metabolizers Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Intermediate Metabolizers Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Patient Understanding of Pharmacogenomics Perceived RR -No tamoxifen/EM	47 percent chance of recurrence Interval 0.0 to 100.0	—	—	—
Patient Understanding of Pharmacogenomics Perceived RR -No tamoxifen/iM	48 percent chance of recurrence Interval 0.0 to 100.0	—	—	—
Patient Understanding of Pharmacogenomics Perceived RR -No tamoxifen/PM	53 percent chance of recurrence Interval 0.0 to 100.0	—	—	—
Patient Understanding of Pharmacogenomics Perceived RR - tamoxifen/EM	22 percent chance of recurrence Interval 0.0 to 100.0	—	—	—
Patient Understanding of Pharmacogenomics Perceived RR -tamoxifen/IM	30 percent chance of recurrence Interval 0.0 to 100.0	—	—	—
Patient Understanding of Pharmacogenomics Perceived RR -tamoxifen/PM	40 percent chance of recurrence Interval 0.0 to 100.0	—	—	—

Adverse Events

Ultra-rapid and Extensive Metabolizers

Serious events: 0 serious events

Other events: 149 other events

Deaths: 0 deaths

Intermediate Metabolizers

Serious events: 3 serious events

Other events: 274 other events

Deaths: 0 deaths

Poor Metabolizers

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Ultra-rapid and Extensive Metabolizers n=161 participants at risk Those with the highest endoxifen concentrations as measured at baseline.	Intermediate Metabolizers n=290 participants at risk Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Poor Metabolizers n=29 participants at risk Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Reproductive system and breast disorders Hemorrhage, GU	0.00% 0/161 • Approximately ten months from on-study to last follow-up visit	0.34% 1/290 • Number of events 1 • Approximately ten months from on-study to last follow-up visit	0.00% 0/29 • Approximately ten months from on-study to last follow-up visit
Psychiatric disorders Mood alteration	0.00% 0/161 • Approximately ten months from on-study to last follow-up visit	0.34% 1/290 • Number of events 1 • Approximately ten months from on-study to last follow-up visit	0.00% 0/29 • Approximately ten months from on-study to last follow-up visit
Vascular disorders thrombosis	0.00% 0/161 • Approximately ten months from on-study to last follow-up visit	0.34% 1/290 • Number of events 1 • Approximately ten months from on-study to last follow-up visit	0.00% 0/29 • Approximately ten months from on-study to last follow-up visit
Nervous system disorders headache	0.00% 0/161 • Approximately ten months from on-study to last follow-up visit	0.34% 1/290 • Number of events 1 • Approximately ten months from on-study to last follow-up visit	0.00% 0/29 • Approximately ten months from on-study to last follow-up visit

Other adverse events

Additional Information

Robin V. Johnson

UNC Lineberger Comprehensive Cancer Center

Phone: 919-966-1125

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place