Aubert RE et al. ASCO 2009; Abstract CRA508. (Oral Presentation) Increased Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen with CYP2D6 Inhibitors Aubert RE et al. ASCO 2009; Abstract CRA508. (Oral Presentation)

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

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 Women with BC who were TAM naïve prior to TAM initiation (N = 26,045)* Continuous eligibility 6 months pre-index Rx and TAM naïve (N = 6,966) TAM in possession for 24 months and adherence of at least 70% and breast cancer diagnosis (N = 1,659) CYP2D6 inhibitor weak or without overlap with TAM therapy N = 355 No CYP2D6 inhibitor therapy N = 945 Concomitant moderate-potent CYP2D6 inhibitor overlapping with TAM N = 359 * 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.

Primary Study Endpoint and Statistical Analyses 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 Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Results: Risk of Breast Cancer Recurrence with Moderate/Potent CYP2D6 Inhibitor Use Cohort N 2yr Recurrence Rate Hazard 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 *Total N = 410; 3 observations excluded with event occurring before CYP2D6 inhibitor exposure **CYP2D6 inhibitor determination established by more than one of the following reference materials: PGx handbook, FDA, P450 Drug Interaction Table (Flockhart), Lexicomp/Micromedex Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Results: Moderate/Potent, but Not Weak, SSRI Inhibitors Associated with Reduced Event-Free Survival Cohort Event-Free Survival Hazard 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 Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Summary and Conclusions 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) Source: Aubert RE et al. ASCO 2009; Abstract CRA508.

Dezentjé V et al. ASCO 2009; Abstract CRA509. (Oral Presentation) Concomitant CYP2D6 Inhibitor Use and Tamoxifen Adherence in Early-Stage Breast Cancer: A Pharmacoepidemiologic Study Dezentjé V et al. ASCO 2009; Abstract CRA509. (Oral Presentation)

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

Study Population Patients (N = 3,147) Eligible (N = 1,962) Tamoxifen only N = 1,749 TAM plus CYP2D6 inhibitor N = 213 ≥ 60 days CYP2D6 inhibitor use N = 150 Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

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 In a subset analysis, patients receiving strong CYP2D6 inhibitors did not experience a greater risk of breast cancer recurrence Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

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 *Adjusted for size, nodal status and diagnostic year Source: Dezentjé V et al. ASCO 2009; Abstract CRA509.

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

Limitations of the Aubert and Dezentje Studies 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 Source: Sterns V. ASCO 2009; Breast Local-Regional and Adjuvant Therapy Discussion.

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