Authors: Thais Abreu de ALMEIDA 1, Institution:

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1 Correlation of CYP2D6 s genotype and phenotype with clinicopathological characterization and impact on survival in Brazilian breast cancer population: a prospective study. Authors: Thais Abreu de ALMEIDA 1, Jeanine Marie NARDIN 1, Angela DASENBROCK 1, Elisa GAIO 1, Raquel SKRSYPCSAK 1, Lucia de NORONHA 2, Hiltrud BRAUCH 3, José Claudio CASALI DA ROCHA 1 Institution: 1.Hospital Erasto Gaertner Liga Paranaense de Combate ao Câncer; 2.Pontifícia Universidade Católica do Paraná (PUC-PR); 3.Institut für Klinische Pharmakologie (IKP)

2 Breast Cancer Risk Factors (50%) Genetic Factors (10% germinative mutations) Variable Presentation Treatment Response Prognosis Modifiers of Risk and Prognosis? Epigenetics Factors. BRADLEY, C. J.; GIVEN, C. W.; ROBERTS, C. Race, socioeconomic status, and breast cancer treatment and survival. Journal of the National Cancer Institute, v. 94, n. 7, p , 2002.

3 Cytochrome P450 Metabolic activation Activation Inactivation Tumor development and progression Nature Reviews Cancer 6, (December 2006)

4 Tamoxifen Selective Modulator Estrogen Receptor (ER) 2/3 breast cancer are hormonal receptor positive (HR+) 41% anual recurrence reduction 34% death risk reduction Early breast cancer trialists collaborative, Lancet 365(9472): , 2005

5 LYON, E.; GASTIER FOSTER, J.; PALOMAKI, G. E.; et al. Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy. Genetics in Medicine, v. 14, n. 12, p doi: /gim , 2012.

6 Breast Care 2008;3:43 50

7 CYP2D6 genotyping: does it matters? ATAC e BIG 1-98 NO correlation CYP2D6 genotype and tamoxifen response Rae, JM. et al. J Natl Cancer Inst. 104:452-60, 2012 Regan, MM. et al. J Natl Cancer Inst. 104: ,2012 BUT Genotyping error technics Retrospective analyses Goldberg, P. et al. Cancer Letter. 38: Brauch, H. et al. J Clin Oncol. 31: Goetz, M.P. et al. J Natl Cancer Inst. 106(5):2014

8 CYP2D6 genotyping: matters! Schroth, W. et al. J Clin Oncol. 25(33): , 2008

9 Endpoints Determine the frequencies of the CYP2D6 s phenotype in brazilian women with breast cancer; Correlation of CYP2D6 s phenotype with clinicopathological characterization; Correlation of CYP2D6 s phenotype with overall survival and disease-free survival.

10 Methodology Prospectively, 363 subjects with breast cancer were recruited Inclusion criteria Female breast cancer patients, 18 years (any stage, newly diagnosed, with no treatment) Pre or post menopausa Any molecular, hystological ou IHC type Exclusion criteria Patients that have received any sistemic treatment Patients with a second primary cancer

11 Methodology Clinicopathological data were registered, and blood sample was collected at first visit. CYP2D6 genotyping was performed in 188 subjects - 8 alleles using MALDI-TOF and Taqman.

12 - CYP2D6 alleles: *1, *3, *4, *5, *9, *10, *41, *17 Methods Classification Normal function Reduced-function Non-function Alleles CYP2D6*1, CYP2D6*2 CYP2D6*10, CYP2D6*17 CYP2D6*3, CYP2D6*4 CYP2D6*5, CYP2D6*6 Phenotype UM: Ultra rapid (increased) EM: Extensive (normal) Homozygous Heterozygous IM: Intermediate (reduced) PM: Poor (absent) Characteristics Gene duplication 2 normal funcion alleles 1 normal function allele Reduced-function allele homozygous or IM/PM Non-function allele homozygous Katz, A. et al. Feb.2010

13 Methods Phenotype interpretation CYP2D6 Score Allelic Phenotype Combination Phenotype 0 PM/PM PM 0,5 PM/IM IM 0,75 IM/IM IM 1 EM/PM hetem 1,5 EM/IM hetem Phenotype Interpretation Reduced Metabolism 2 EM/EM EM Normal 3 EM/UM UM Metabolism ZINEH, I.; BEITELSHEES, A. L.; GAEDIGK, A.; et al. Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clinical Pharmacology and Therapeutics, v. 76, n. 6, p doi: /j.clpt , 2004.

14 Methods Statistics CYP2D6 s phenotype correlations: Quantitative variables: Student s t-test or Mann-Whitney. Qualitative variables: Fisher s exact test or Chi-square test. Survival: Kaplan-Meier (log-rank test) Disease-free survival: Fine and Gray model (death: competitive risk) p<0.05 Analysis: Stata v Hardy Weinberg equilibrium (HWE) tested.

15 Results Median follow-up of 40 months 363 subjects were recruited 188 genotype analysed

16 CYP2D6 s Genotype EM (45,7%) PM (1,6%)

17 CYP2D6 s phenotype and clinicopathological correlation Characteristics Geral CYP2D6 reduced metabolism a CYP2D6 normal metabolism b (n=363) (n=94) (n=94) p valor c Race, No. (%) White 265 (73) 69 (73.4) 68 (72.4) Black 13 (3.5) 2 (2.1) 4 (4.3) Pardo/mulato 83 (23) 23 (24.5) 20 (21.3) Asian/yellow 1 (0.25) 0 (0) 1 (1) Indian 1 (0.25) 0 (0) 1 (1) Age in years, median (range) 54 (24-91) 52 (31-87) 53 (29-89) 0,601 Status menopausal, No. (%) Premenopausal 138 (38) 39 (41.5) 35 (37.3) Postmenopausal 225 (62) 55 (58.5) 59 (62.7) Performance Status, No. (%) 0 or (94.8) 89 (94.7%) 87 (92.5) 0,766 2, 3 or 4 19 (5.2) 5 (5.3%) 7 (7.5) TNM, No. (%) 0 (in situ) 4 (1.1) * * IA/IB 81 (22.3) 22 (23.6) 26 (27.7) 0,399 IIA/IIB 159 (43.8) 46 (49.4) 42 (44.7) IIIA/IIIB/IIIC 86 (23.7) 13 (14) 19 (20.2) IV 33 (9.1) 12 (13) 7 (7.4) Treatment Propose neoadjuvant 153 (42,1) 37 (39.3) 39 (41.5) 0,480 adjuvant 177 (48.8) 45 (47.9) 48 (51.1) paliative 33 (9.1) 12 (12.8) 7 (7.4) CYP, cytochrome p450; TNM (AJCC, 2010). a. CYP2D6 reduced metabolism: PM, IM, hetem. b CYP2D6 normal metabolism: EM, UM. c t-student for independent variables or Mann-Whitney (quantitative variables); Fisher s exact test or Chi-square teste (qualitative variable); p<0,05.

18 Characteristics Geral CYP2D6 reduced metabolism a CYP2D6 normal metabolism b (n=363) (n=94) (n=94) p valor Grade d, No.(%) - G1 30 (8.3) 10 (10.6) 7 (7.5) G2 175 (48.2) G3 53 (14.6) 56 (59.6) 64 (68) Gx 105 (28.9) 28 (29.8) 23 (24.5) Histology - Ductal carcinoma in situ 4 (1.1) 1 (1) 0 (0) Invasive carcinoma of no special type 306 (84.3) 84 (89.4) 77 (82) Invasive lobular carcinoma 18 (5) 3 (3.2) 7 (7.4) Invasive ducto-lobular carcinoma 10 (2.8) 1 (1) 4 (4.3) Tubular carcinoma 2 (0.6) 1 (1) 0 (0) Mucinous carcinoma 10 (2.8) 1 (1) 4 (4.3) Medullary carcinoma 1 (0.3) 0 (0) 0 (0) Invasive papillary carcinoma 4 (1.1) 1 (1) 1 (1) Others 8 (2) 2 (2.4) 1 (1) HR, No. (%) positive 256 (71.1) 79 (84.9) 75 (79.8) 0,443 negative 104 (28.9) 14 (15.1) 19 (20.2) HER2, No. (%) positive 65 (18.1) 19 (20.4) 19 (20.2) 1,000 negative 295 (81.9) 74 (79.6) 75 (79.8) Triple Negative, No. (%) Yes 68 (18.9) 7 (7.5) 8 (8.5) 1,000 No 292 (81.1) 86 (92.5) 86 (91.5) Ki67 14% 100 (27.9) 29 (31.2) 34 (36.2) 0,536 > 14% 259 (72.1) 64 (68.8) 60 (63.8)

19 Overall Survival 40 months follow up (363 patients) Kaplan-Meier Overall survival curve 1,0 0,9 0,8 Proporção Proportion acumulada 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0, Tempo de sobrevida (meses) Survival (months) Overall Survival all patients (n=363) Tempo Time (months) (meses) % Survival de sobrevida* (%) 0 100% 6 98,1% 9 98,1% 12 96,9% 18 94,7% 24 90,4% 36 88,5% 40 88,5% *Kaplan-Meier.

20 CYP2D6 s Phenotype CYP2D6 Score Allelic Combination Phenotype n (%) n (%) 0 PM/PM PM 3 (1.6) 0,5 PM/IM IM 12 (6.4) Phenotype Interpretation 0,75 IM/IM IM 2 (1.1) Reduced 1 EM/PM hetem 48 (25.5) Metabolism 1,5 EM/IM hetem 29 (15.4) 2 EM/EM EM 86 (45.7) Normal 3 EM/UM UM 8 (4.3) Metabolism CYP2D6 Group Score 0; 0,5; 0,75 PM/PM, PM/IM, IM/IM PM/IM 17 (9.0) Reduced 1; 1,5 EM/PM, EM/IM hetem 77 (41.0) Intermediary 2; 3 EM/EM, EM/UM EM 94 (50.0) Normal Total 188 (100)

21 Survival and CYP2D6 s Phenotypes 1,00 0,95 Proporção acumulada 0,90 0,85 0,80 0,75 0,70 p =0,856 PM/IM EM (n=17) hetem (n=94) (n=77) 0,65 0,60 0,55 0, Tempo de sobrevida (meses)

22 Survival and CYP2D6 s Phenotypes and HR status 1,00 0,95 Metabolismo extensivo e RH positivo (n=75) 0,90 Metabolismo reduzido e RH positivo (n=79) Proporção acumulada 0,85 0,80 0,75 0,70 0,65 p = 0,122 Metabolismo reduzido e RH negativo Metabolismo extensivo e RH negativo (n=14) (n=19) 0,60 0,55 0, Tempo de sobrevida (meses)

23 Survival and CYP2D6 s Phenotypes and Staging Proporção acumulada 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Metabolismo reduzido e TNM estadio I/II Metabolismo extensivo e TNM estadio I/II Metabolismo extensivo e TNM estadio III Metabolismo reduzido e TNM estadio III Metabolismo reduzido e TNM estadio IV Metabolismo extensivo e TNM estadio IV (n=68) (n=68) (n=19) (n=13) (n=12) (n=7) 0, Tempo de sobrevida (meses)

24 Disease-free Survival and CYP2D6 s Phenotypes Disease-free survival at 12 months: 96,3% Disease-free survival was not influenced by CYP2D6 s phenotypes (EM vs. hetem vs. PM/IM) (p=0,730 e p=0,999, respectively).

25 Conclusion At this moment, there is no association between CYP2D6 s phenotypes and clinicopathological characteristics CYP2D6 phenotypes did not influenced overall survival and disease-free survival. Further follow-up data will analyze this cohort (363 patients) at 50 months and in a subset of estrogen receptor positive group. Thank s to all patients