Abstract P5-12-05: Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations
Authors: Panuganty Veera Durga Sravanthi , Keller Denise , Teft Wendy A , Lenehan John Gordon , Potvin Kylea Raijann , Younus Jawaid , Vandenberg Theodorus Anthony , Logan Diane Mary , Hahn Karin , Brackstone Muriel , Blanchette Phillip Stanley , Perera Francisco , Choi Yun-Hee , Kim Richard Brian 
Published: March 2020

Background: Tamoxifen is widely used in patients with hormone sensitive breast cancer in the adjuvant setting to decrease risk of recurrence and metastasis. 5-10 years of tamoxifen has demonstrated a near 50% reduction in recurrence risk. Despite marked interpatient variation in the metabolism of tamoxifen to its active metabolite endoxifen, all patients are prescribed 20 mg daily dose of tamoxifen. Current evidence suggests that patients are at risk for suboptimal benefit if measured endoxifen concentration is below 5.9 ng/ml (~15nM). However, there have been conflicting data on the clinical utility of CYP2D6 genotype testing, and measuring endoxifen plasma concentration as a predictor of breast cancer recurrence. The goal of this prospective study was to determine the impact of endoxifen levels and CYP2D6 genetic variations to clinical outcome among patients with early breast cancer.

Methods: Since 2010, as part of Personalized Medicine Program in Oncology, our team has been prospectively enrolling patients on tamoxifen therapy. To date 950 patients have been enrolled and preliminary analysis has been completed in 429. After initial CYP2D6 genotype testing, plasma concentration of tamoxifen and its metabolites were quantified using liquid chromatography-tandem mass spectrometry during each clinic visit. Baseline characteristic are outlined in table 1. Primary outcome assessed was invasive disease-free survival (IDFS) defined as time since start of tamoxifen therapy till an event of interest such as loco-regional recurrence, distant metastasis, new contralateral primary breast cancer, death due to breast cancer and other causes. Patients were censored at their last encounter at our institution (London Health Sciences Centre).

Results: IDFS data for 426 patients were obtained. Outcome was stratified by CYP2D6 phenotypes (ultra-rapid, extensive, intermediate and poor metabolizers) and endoxifen levels (&gt;5.9ng/ml or &lt;5.9ng/ml). CYP2D6 phenotype did not demonstrate a significant association for IDFS. However, Kaplan Meier analysis stratified for endoxifen concentration &gt;vs&lt; 5.9 ng/ml showed a clear trend towards lower IDFS (hazard ratio = 2.4, (95%CI,1.26-4.77) P=0.0002) among those with endoxifen &lt; 5.9 ng/ml. We note this preliminary data analysis was unadjusted and will undergo further in-depth statistical analysis.

Conclusion: Preliminary finding suggests endoxifen concentration, but not CYP2D6 phenotype, may be a predictor of risk for suboptimal benefit during tamoxifen therapy. Detailed statistical analysis is planned for the full cohort, including adjustment for covariates including tumor stage, menopausal status, drug interactions, and use of aromatase inhibitors. To our knowledge, this is the first study of its type to prospectively collect multiple plasma samples for tamoxifen and endoxifen level in real-world patients during tamoxifen therapy, with sufficient sample size and follow-up period for primary clinical outcome.

Table 1: Baseline Characteristics of PatientsCharacteristicsCYP2D6-Phenotypes, n=429 (%)Endoxifen concentration, n=429 (%)UM/EMIMPM&gt;5.9ng/ml(~15nm)&lt;5.9ng/ml(~15nm)n= 256n= 153n= 20n=376n= 53Age at DiagnosisMean5049485048Range24-8928-7928-8324-8427-88SexMale3 (1)7(5)08(2)2(4)Female253 (99)146(95)20(100)368(98)51(96)Tumor statusT1121(47)70(46)9(45)177(47)23(43)T297(38)58(38)10(50)142(38)23(43)T318(7)16(10)1(5)30(8)5(9)T412(5)4(3)016(4)0unknown8(3)5(3)011(3)2(4)Nodal statusN0124(97)71(46)10(50)179(48)26(49)N195 (37)53(35)9(45)144(38)13(24)N217(7)18(12)1(5)28(7)8(15)N313(5)5(3)015(4)3(6)Unknown7(3)6(4)010(3)3(6)HistologyIDC205(80)128(84)16(80)303(81)48(91)ILC28(11)14(9)3(15)41(11)3(6)other5(2)2(1)06(2)0unknown18(7)9(6)1(5)26(7)2(4)Grade154(21)24(16)3(15)78(21)3(6)2139(54)84(55)13(65)202(54)34(64)354(21)39(25)4(20)84(3)13(24)unknown9(4)6(4)012(3)3(6)ER+251(98)151(99)20(100)369(98)53(100)-5(2)2(1)07(2)0unknown00000PR+232(90)142(93)20(100)343(91)51(96)-24(9)11(7)033(9)2(4)unknown00000Her2+55(21)25(16)5(25)75(20)10(19)-200(78)127(84)15(75)299(80)43(81)unknown1102(1)0Breast SurgeryMastectomy149(58)84(55)11(55)214(57)30(57)Lumpectomy105(41)68(44)9(45)159(42)23(43)Unknown2(1)103(1)0Axillary SurgerySLNB137(54)80(52)12(60)204(54)25(47)ALND113(44)70(46)8(40)165(44)26(49)Unknown6(2)3(2)07(2)2(4)Chemotherapy190(74)108(71)16(80)277(74)37(70)Radiation Therapy213(83)126(82)17(85)310(82)46(87)Herceptin57(22)23(15)6(30)77(16)9(17)

Citation Format: Veera Durga Sravanthi Panuganty, Denise Keller, Wendy A Teft, John Gordon Lenehan, Kylea Raijann Potvin, Jawaid Younus, Theodorus Anthony Vandenberg, Diane Mary Logan, Karin Hahn, Muriel Brackstone, Phillip Stanley Blanchette, Francisco Perera, Yun-Hee Choi, Richard Brian Kim. Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-05.