# Presentation: 789721

## Tamoxifen Pharmacogenetics and Prediction of Breast Cancer Relapse After Administration of Tamoxifen

- Matthew P. Goetz, MD
- Assistant Professor of Oncology
- Mayo Clinic College of Medicine

**CP1229323-1**

**David Flockhart, MD, PhD**
**Consortium on Breast Cancer Pharmacogenomics (COBRA) Pharmacogenomics Research Network**

## Breast Cancer2006 (USA)

- Invasive Breast Cancer:  212,920 New Cases
- Ductal Carcinoma in Situ:   61,980 Cases
- 2/3 are estrogen positive—Candidates for hormonal therapy

- Jemal A, et al. CA Cancer J Clin 2006;56;106-30

## Tamoxifen

- The most important drug worldwide for hormone receptor positive breast cancer
- Approved by the FDA for treatment of
- High-risk patients
- DCIS
- Pre and Postmenopausal breast cancer
- Metastatic disease
- Most commonly used hormonal therapy in early and advanced male breast cancer

**CP1229323-2**

## Tamoxifen and Breast Cancer

***Tamoxifen and Breast Cancer***
*FDA-Approved Indications*

- 1977

- 2000

- Postmenopausal
- Metastatic

- DCIS

- ‘86

- Adjuvant Postmenopausal Node+

- Premenopausal Metastatic

- ‘89

- ‘90

- Adjuvant Node-negative

- ‘93

- Male Metastatic

- “Prevention”

- ‘98

## Tamoxifen (for ~5 yrs) in Early Breast Cancer

**CP1193154-1**

- EBCTCG:  Lancet 365:1687, 2005

- Recurrence (%)

**Years**

**Control**
**45-0%**

**About **
**5 years of **
**tamoxifen 33.2%**

**38.3**

**26.5**

**24.7**

**15.1**

**Tamoxifen (for ~5 yrs) in Early Breast Cancer**
**Oxford Meta-analysis*  **

***10,386 women**

**Hazard Ratio (Control/Tamoxifen)**
** ****= ~1.69**

## Adjuvant Hormonal Therapy: Designs of Recent Major Trials 

**CP1157143-1**

**Switching**

**Tamoxifen**

**Aromatase Inhibitor**

**Placebo**

**Initial Adjuvant Therapy**

**5 yr**

**2-3 yr**

**2-3 yr**

**5 yr**

**~5 yr**

**Extended Adjuvant Therapy**

_**DFS HR**_

**0.57**

_**DFS HR**_

_**DFS HR**_

**0.68**

**0.83**

## Adjuvant hormonal therapy

- Pre-menopausal
-  Tamoxifen for 5 years

- Postmenopausal
-    Aromatase inhibitor for 5 years or...
-    Tamoxifen for 2-3 yrs followed by an AI

## ATAC: Recurrences before 2.5 years

**Proportion with recurrence (%)**

**0**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**48**

**54**

**HR****	****95% CI****	*****p*****-value**

**AN vs TAM****	****0.78****	****     0.65–0.93       0.007**

*** ****	****Censoring non-BC deaths before recurrence**

**Time to event (months)**

**No. of**
**Pts. at risk**

**AN**
**TAM**

**2617**
**2598**

**2533**
**2516**

**2436**
**2386**

**2243**
**2180**

**1258**
**1210**

**602**
**574**

**Howell A, EBCC Hamburg 3-18-2004**

**Absolute difference  1.6%**

## Is there a better way to identify 

- patients for whom tamoxifen or anastrozole
- would be the preferred drug for initial
- adjuvant endocrine therapy?

## Tamoxifen Metabolic Pathway

- Jin, Y. et al. J Natl Cancer Inst 2005;97:30-39

**CP1229323-3**

## Concentration

**Endoxifen and 4-OH-Tamoxifen are Equipotent as Inhibitors of Estrogen Stimulated Cell Proliferation**

**Concentration**

**Cell Growth**

- Johnson MD, et al: Breast Cancer Res Treat 85:151-9, 2004

## Endoxifen and 4-OH tamoxifen

- Same
- potency in ER binding1
- Suppression of ER-dependent MCF-7 proliferation2
- global ER-responsive gene expression3
- Different
- Endoxifen concentrations 10 fold higher than 4-hydroxy tamoxifen4

**1. Johnson et al. ****Breast Cancer Res Treat 2004.**
**2.  Lim YC, Cancer Chemother Pharmacol 2005;.**
**3.  Lim YC, et al. J Pharmacol Exp Ther 2006;In Press.**
**4.  Stearns Vet al. J Natl Cancer Inst 2003**.

## Tamoxifen Metabolic Pathway

**CP1229323-3**

**Jin Y et al:  J Natl Cancer Inst 97:30, 2005**

## CYP2D6 Genotype and Endoxifen

**CP1229323-4**

**Jin Y et al:  J Natl Cancer Inst 97:30, 2005**

**CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state)**

**P<0.001, r****2****=0.24**

**Plasma   Endoxifen **
**(nM)**

## NCCTG 89-30-52

**CP1229323-5**

- RANDOMIZATION

- Postmenopausal women
- Early ER+ breast cancer
- 541 women accrued

- 5 years tamoxifen +1 year fluoxymesterone(n=285)

- 5 years of tamoxifen(n=256)

- Ingle et al. Breast Cancer Res Treat. 2006 Mar 15

## NCCTG 89-30-52

- Surgically resected stage I-III breast cancer
- All tumors were estrogen receptor positive
- ≥10 fmol/mg cytosol protein positive or
- positive by immunohistochemical assay
- No adjuvant chemotherapy allowed
- Median follow-up of 11 years
- Accrual completed in April 1995
- No differences in RFS or OS

- Ingle et al. Breast Cancer Res Treat. 2006 Mar 15

## CYP2D6*4 Genotyping

- Tamoxifen monotherapy arm (256 patients)
- Formalin-fixed paraffin-embedded tumor blocks (223 patients)
- CYP2D6*4 (n=190)
- Wt/Wt – 137 (72%)
- Wt/*4 – 40 (21%)
- *4/*4 – 13 (7%)

**CP1229323-6**

**Goetz, Rae et al:  J Clin Oncol 23:9312, 2005**

## Relapse-free Time

**%**

**Years after randomization**

**CYP2D6 Wt/Wt**

**Relapse-free Time**

**CYP2D6 *4/Wt**

**CP1193836-1**

**CYP2D6 *4/*4**

**P=0.030**

- Goetz et al J Clin Oncol. 2005;23(36):9312-8.

## Relapse-free Survival

**%**

**Years after randomization**

**Relapse-free Survival**

**CP1193836-2**

**CYP2D6 WT/WT**

**CYP2D6 *4/WT**

**P=0.020**

**CYP2D6 *4/*4**

- Goetz et al J Clin Oncol. 2005;23(36):9312-8.

## Incidence of Moderate or Severe Hot Flashes

| Genotype | % of patients who developed moderate or severe hot flashes |
| --- | --- |
|   

*CYP2D6 *4/*4

*CYP2D6 *4/WT or Wt/WT | 

0%

20% |

- Goetz et al J Clin Oncol. 2005;23(36):9312-8.

## CYP2D6 *4 Genotype and Clinical Outcome (multivariate analysis)

- *4/*4 vs Wt/Wt or Wt/*4
- Time to breast recurrence:  HR* 1.85, p=0.176
- Relapse-free survival:  HR* 1.86, p=0.089

**CP1229323-7**

**	*********	****Adjusted for nodal status, tumor size**
**	****	**
**Goetz, Rae et al:  J Clin Oncol 23:9312, 2005**

## Without Paroxetine

- With Paroxetine

- Stearns V, et al. J Natl Cancer Inst 2003;95(23):1758-64

## Inhibition of CYP2D6 Affects Endoxifen Concentrations

**Inhibition of CYP2D6 Affects Endoxifen Concentrations**

**CP1229323-8**

**Jin Y et al:  J Natl Cancer Inst 97:30, 2005**

**Wt/Wt, no****inhibitor**

**Venlafaxine**

**Sertraline**

**Paroxetine**

***4/*4, no****inhibitor**

**Plasma   Endoxifen **
**(nM)**

## CYP2D6 Inhibitors and BreastCancer Relapse

- Paroxetine, fluoxetine, and venlafaxine significantly reduce the number and severity of hot flashes in tamoxifen-treated women1-3
- 30% tamoxifen-treated patients are prescribed antidepressants for depression or hot flashes4
- Other commonly administered medications also inhibit CYP2D6 (amiodarone, doxepin, cimetidine)
- An analysis of CYP2D6 metabolism in tamoxifen treated patients is incomplete without accounting for CYP2D6 inhibitors

**CP1229323-9**

*1.* Loprinzi CL et al.  Lancet 2000;356:2059–63.
*2.* Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83.
*3. *Stearns et al. JAMA 2003;289:2827–34.
*4. * Love et al.  Patterns of Care in Medical Oncology (2005)

## NCCTG 89-30-52

**CP1229323-5**

- RANDOMIZATION

- Postmenopausal women
- Early ER+ breast cancer
- 541 women accrued

- 5 years tamoxifen +1 year fluoxymesterone(n=285)

- 5 years of tamoxifen(n=256)

- Ingle et al. Breast Cancer Res Treat. 2006 Mar 15

## Methods

- 225 Charts were reviewed at each randomizing site to ascertain medication history
- Potent CYP2D6 inhibitors:  Fluoxetine and paroxetine
- Moderate CYP2D6 inhibitors:  Sertraline, cimetidine, amiodarone, doxepin, ticlopidine, or haloperidol
- Duration of coadministration:  <1, 1-2, 2-3, 3-4 and 4-5 years
- Statistics:  Log rank test and Cox modeling

**CP1229323-10**

## Methods 

- CYP2D6 metabolism defined by *4 genotype and medication history
- Extensive CYP2D6 metabolism
- Wt/Wt, no inhibitor
- Decreased CYP26 metabolism
-  Wt/*4
- *4/*4
- Any genotype and co-administration (yes/no) of a moderate or potent CYP2D6 inhibitor

## Patient Characteristics

** ****	****Metabolizer status known****	****n=180**
**Median age (range)****	****68 (42-87)**
**ER status (%)****	****100**
**Tumor size (cm)****	****  **
**  **<3 (%)**	****  78**
**  **3 (%)**	****  22**
**Positive nodes**
**  **0 (%)**	****  64**
**  **1-3 (%)**	****  25**
**  **4-9 (%)**	****    7**
**  **10 (%)**	****    4**
**Tumor grade**
**  **1 (%)**	****  24**
**  **2 (%)**	****  54**
**  **3 (%)**	****  15**
**  **Unknown (%)**	****  7**

**CP1229323-13**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Results

**CP1229323-12**

- CYP2D6 metabolism determined in 180 pts (medication history 225 pts)
- Inhibitor status
- Potent inhibitors (n=3)
- Moderate inhibitors (n=10)
- Median duration of use 2-3 years

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Time to Breast Recurrence

**CP1234316-1**

**%**

**Years after randomization**

**P=0.015**

**Extensive**

**Decreased**

**n=115**

**n=65**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Relapse-Free Survival

**CP1234316-3**

**%**

**Years after randomization**

**P=0.007**

**Extensive**

**Decreased**

**n=115**

**n=65**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Overall Survival

**CP1234316-4**

**%**

**Years after randomization**

**P=0.082**

**Extensive**

**Decreased**

**n=115**

**n=65**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Outcomes by Metabolizer StatusMultivariate Analysis*

**	****Hazard ratio (relative to****Outcome****	****extensive metabolizers)****	****P value**
**Time to breast recurrence****	****1.91 (1.05-3.45)****	****0.034**
**Relapse-free survival****	****1.74 (1.10-2.74)****	****0.017**
**Overall survival****	****1.35 (0.83-2.16)****	****0.223**

**CP1229323-19**

- *Adjusted for size, grade and nodal status, ER, PR, HER-2

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Inhibition of CYP2D6 Affects Endoxifen Concentrations

**Inhibition of CYP2D6 Affects Endoxifen Concentrations**

**CP1229323-8**

**Jin Y et al:  J Natl Cancer Inst 97:30, 2005**

**Wt/Wt, no****inhibitor**

**Venlafaxine**

**Sertraline**

**Paroxetine**

***4/*4, no****inhibitor**

**Plasma   Endoxifen **
**(nM)**

## CYP2D6 Metabolism by Genotype and Inhibitor

- Decreased CYP2D6 Metabolism
- Intermediate metabolizers:  n=40
- Wt/*4 and no inhibitor (n=32)
- Wt/Wt and moderate inhibitor (n=8)
- Poor metabolizers:  n=16
- 4/*4 (n=13)
- Any genotype and potent inhibitor (n=3)
- Unknown:  n=9
- Wt/*4 without med history (n=7)
- Unknown genotype and mod inhibitor (n=2)

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Time to Breast Recurrence

**CP1229323-15**

**%**

**Years after randomization**

**Log Rank**
**P=0.019**

**EM**

**IM**

**PM**

**n=115**

**n=40**

**n=16**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Relapse-Free Survival

**Relapse-Free Survival**

**CP1229323-16**

**%**

**Years after randomization**

**2-year RFS**
**EM 98%**
**IM 92%**
**PM 68%**
**Log Rank**
**P=0.009**

**EM**

**IM**

**PM**

**n=115**

**n=40**

**n=16**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Overall Survival

**CP1229323-17**

**%**

**Years after randomization**

**Log Rank**
**P=0.145**

**EM**

**IM**

**PM**

**n=115**

**n=40**

**n=16**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## Outcomes by Metabolizer StatusUnivariate Analysis

**	****Hazard ratio (relative to****Outcome****	****extensive metabolizers)****	****P value**
**Time to breast recurrence**
**  ****PM****	****3.20 (1.37-7.55)****	****0.007**
**  ****IM****	****1.49 (0.68-3.05)****	**** 0.338**
**Relapse-free survival**
**  ****PM****	****2.69 (1.34-5.37)****	****0.005**
**  ****IM****	****1.63 (0.95-2.78)****	****0.075**
**Overall survival****	**
**  ****PM****	****2.00 (0.92-4.17)****	****0.077**
**  ****IM****	****1.40 (0.80-2.43)****	****0.240**

**CP1229323-18**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

## ATAC: Smoothed Hazard Rates for RecurrenceHormone Receptor + patients 

- 0.5

- 1.0

- 1.5

- 2.0

- 2.5

- 3.0

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- Follow-up time (years)

- Anastrozole

- Tamoxifen

- 0

- Annual hazard rates (%)

**Howell, et al. 2004 San Antonio Breast Cancer Symposium***** ***** **

## Hazard Rates for RFS by CYP2D6Metabolizer Status (n=180)

**CP1229323-20**

**Hazard rates**

**Years after randomization**

**Decreased**

**Extensive**

- Goetz et al.  Breast Cancer Res Treat. 2006 (In  press)

**Notes:**
Revised mls 05/22-06

## Conclusion

- In this trial, CYP2D6 metabolism was an independent predictor of clinical outcome in postmenopausal women with ER positive early breast cancer
- The effect of impaired metabolism was most marked in poor metabolizers
- Consistent with clinical data that tamoxifen activation to endoxifen is dependent upon CYP2D6

**CP1229323-21**

## Conclusion

- These data suggest that determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and moderate/potent CYPY2D6 inhibitors should not be co-administered with tamoxifen

**CP1229323-22**

## Acknowledgments

**Mayo Clinic Cancer Center**
**North Central Cancer Treatment Group**
**Pharmacogenetics Research Network**
**COBRA : The Consortium for Breast Cancer Pharmacogenomics:**
**Indiana University School of Medicine**
**University of Michigan **
**Johns Hopkins University**
**Mayo Clinic**
**Baylor College of Medicine**
**Mayo Clinic Breast Cancer SPORE**

## CYP2D6 Individualized Adjuvant Hormonal Study

**Postmenopausal                 women**
**ER positive breast               cancer**
**UM: Ultra-rapid Metabolizer**
**EM: Extensive Metabolizer**
**IM: Intermediate Metabolizer**
**PM: Poor Metabolizer**

**Standard of care   (AI for 5 years)**

**RANDOMI****ZE**

**EM, UM**

**Tam (2.5 years) followed by AI (2.5 years)**     (n=1950)

**AI (5 years total)** (n=1950)

**CYP2D6 Genotyping**

**IM, PM**

**CYP2D6 IM, and PM:  heterozygous or homozygous for *3, *4, *5, *6, *7, *8, *11, *12**