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