Increased Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen with CYP2D6 Inhibitors

Aubert RE et al.ASCO 2009; Abstract CRA508. (Oral Presentation)

Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Introduction

Tamoxifen (TAM) is metabolized to its active form, endoxifen, by hepatic cytochrome P450 2D6 (CYP2D6)

Diminished CYP2D6 function, both by genetic variation or concurrent use of pharmacologic inhibitors:– Can significantly reduce endoxifen plasma concentrations– May lead to reduced TAM effectiveness

Recent studies with CYP2D6 inhibitors and TAM show reductions in endoxifen, but have not clearly delineated their impact on breast cancer recurrence

Current study objective:

– Investigate the association of the concomitant use of CYP2D6 inhibitors with breast cancer recurrence in women receiving TAM for secondary prevention

Metabolic Relationship Between Tamoxifen, CYP2D6 and Endoxifen

Source: Adapted with permission from Dezentje V. ASCO 2009; Abstract CRA509.

Retrospective Cohort Analysis of Medical and Pharmacy Claims Data

* Taken from medical/pharmacy claims data collected over a 30-month period

(Medco Health Solutions: ICD-9 and CPT-4 codes)Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Women with BC who were TAM naïve prior to TAM initiation (N = 26,045)*

CYP2D6 inhibitor weakor without overlap with

TAM therapyN = 355

Continuous eligibility 6 months pre-index Rx and TAM naïve (N = 6,966)

No CYP2D6 inhibitor therapyN = 945

Concomitant moderate-potent CYP2D6 inhibitor overlapping with TAM

N = 359

TAM in possession for 24 months and adherence of at least 70%and breast cancer diagnosis (N = 1,659)

Primary Study Endpoint and Statistical Analyses

Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Primary Endpoint: Hospitalization for breast cancer during the follow-up period, as determined by ICD-9 diagnosis and CPT-4 procedural code

Incidence and risk of primary endpoint determined for:

– No CYP2D6 inhibitor (n = 945; reference cohort)

– Moderate-potent CYP2D6 inhibitor (n = 359)

– Selective serotonin reuptake inhibitors (SSRI) subgroups

– Moderate-potent inhibitors (fluoxetine, paroxetine, sertraline) (n = 213)

– Weak inhibitors (citalopram, escitalopram, fluvoxamine) (n = 137)

Event-free survival

Results: Risk of Breast Cancer Recurrence with Moderate/Potent

CYP2D6 Inhibitor Use

Cohort N

2yrRecurrence

RateHazard ratio P value

No CYP2D6 inhibitor 945 7.5% Reference NA

Moderate-potent CYP2D6 inhibitor (multiple reference source)**

407* 14.0% 1.92 0.0002

Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

*Total N = 410; 3 observations excluded with event occurring before CYP2D6 inhibitor exposure

**CYP2D6 inhibitor determination established by more than one of the followingreference materials: PGx handbook, FDA, P450 Drug Interaction Table (Flockhart),Lexicomp/Micromedex

Results: Moderate/Potent, but Not Weak, SSRI Inhibitors Associated with Reduced Event-Free Survival

Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

CohortEvent-Free

SurvivalHazard ratio P-value

No CYP2D6 inhibitor (n = 945)

7.5% Reference NA

SSRI weak CYP2D6 inhibitor (n = 137)

8.8% 1.07 0.677

SSRI Moderate/Potent CYP2D6 inhibitor (n = 213*)

16.0% 2.20 0.0002

* 1 observation excluded with event occurring before CYP2D6 inhibitor exposure

Summary and Conclusions

Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Moderate-potent CYP2D6 inhibitors used concomitantly with TAM were associated with a 92% greater risk of BC recurrence versus TAM alone

SSRIs made up the single largest class of moderate-potent CYP2D6 inhibitors in this study

– Moderate-potent inhibitors were associated with a 120% increased risk of BC recurrence

– Weak inhibitors were not associated with increased risk

Combined use of TAM and specific moderate-potent CYP2D6 inhibitors can reduce the effectiveness of TAM in preventing BC recurrence

These findings may advise clinicians on the selection of concomitant therapy in women on TAM, in particular for SSRIs

Additional research is needed to explore the impact of therapeutic alternatives to SSRIs (such as SNRIs)

Concomitant CYP2D6 InhibitorUse and Tamoxifen Adherence in Early-Stage Breast Cancer: A Pharmacoepidemiologic Study

Dezentjé V et al.ASCO 2009; Abstract CRA509. (Oral Presentation)

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

Introduction

Concomitant use of CYP2D6 inhibitors, such as the commonly prescribed SSRIs, as well as low tamoxifen (TAM) adherence may negatively impact TAM efficacy in breast cancer

Current study objectives:– Relate concomitant CYP2D6 inhibitor use to breast

cancer recurrence– Relate TAM adherence to breast cancer recurrence

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

Methods and Patients

Retrospective follow-up study

Databases and records analyzed: PHARMO, PALGA, Dutch Medical Register (LMR)

Patients screened for > 60 days concomitant use of 9 possible CYP2D6 inhibitors

Adherence assessed as proportion of days covered with available TAM over one year (days covered/365 x 100)

Event = distant metastasis, locoregional recurrence, second primary breast cancer

Inclusion Criteria: Breast cancer patients who were treated with TAM as adjuvant therapy between 1994 and 2006

Exclusion Criteria: Metastatic disease

Study Population

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

Tamoxifen onlyN = 1,749

Eligible (N = 1,962)

Patients (N = 3,147)

TAM plus CYP2D6 inhibitorN = 213

≥ 60 days CYP2D6 inhibitor use

N = 150

Results: CYP2D6 Inhibitor Use

Difference in risk of breast cancer recurrence between CYP2D6 inhibitor users and non-users

CYP2D6 inhibitor use Hazard Ratio 95% CI P value

No use (n = 1,749) 1.00 — —

Use ≥ 60 days (n = 150) 0.95 0.60 – 1.50 0.73

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

• In a subset analysis, patients receiving strong CYP2D6 inhibitors did not experience a greater risk of breast cancer recurrence

Results: Adherence

Relationship between tamoxifen adherence and breast cancer recurrence

Adherence (365 days)Adjusted

Hazard Ratio* 95% CI P value

≥ 80% vs < 80% days covered

0.69 0.46 – 1.02 0.064

≥ 90% vs < 90% days covered

0.67 0.48 – 0.93 0.016

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

*Adjusted for size, nodal status and diagnostic year

Summary and Conclusions

Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

This study demonstrated no association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant TAM

First report that poor TAM adherence among patients with early breast cancer is associated with reduced event-free time

Limitations of the Aubert and Dezentje Studies

Source: Sterns V. ASCO 2009; Breast Local-Regional and Adjuvant Therapy Discussion.

Retrospective analyses

Relatively small sample sizes

Limited follow-up

Incomplete accountability for BC recurrence

CYP2D6 genotype not available

Reasons for inhibitor use unknown

Aubert study: Claims data limited, excluded women with early recurrences or low medication possession rate

Dezentje study: Short concomitant medication use

Implications

Source: Sterns V. ASCO 2009; Breast Local-Regional and Adjuvant Therapy Discussion.

Concomitant use of CYP2D6 inhibitors may influence TAM-associated outcomes

Additional studies incorporating both genetic variants and inhibitors are required

– CYP2D6 variants may influence TAM-associated symptoms (JCO 2005;23:9312) or adherence to treatment (Pharmacogenomics J 2009;9:258)

– Investigation of the influence of inhibitors on endoxifen is ongoing (Goetz, NCT00667121)

Concomitant use of CYP2D6 inhibitors should be limited in patients receiving TAM

Women who are candidates for TAM may be considered for CYP2D6 testing