TRATAMIENTO COMPLEMENTARIO SISTEMICO CON QUIMIOTERAPIA. Miguel Martín Hospital Universitario Gregorio Marañón Madrid

Transcripción

1 TRATAMIENTO COMPLEMENTARIO SISTEMICO CON QUIMIOTERAPIA Miguel Martín Hospital Universitario Gregorio Marañón Madrid

2 Quimioterapia Adyuvante del CM: Evolución 100% SUPERVIVENCIA LIBRE DE ENFERMEDAD 50% Pacientes con Ganglios Positivos 26% 0% añosa Bonadonna, 1992; EBCTG, 2000; Citron, JCO 2003; Martin, NEJM 2005;

3 Quimioterapia (QT) adyuvante del CM: Aspectos clave Selección de pacientes para QT basado en riesgo de recaída sin QT Selección del esquema de QT para un paciente individual: mejor fármaco/régimen ( QT individualizada?) toxicidad aguda y crónica del régimen enfermedades concomitantes y expectativa de vida del paciente

4 Tratamiento Adyuvante del Cáncer C de Mama: Perspectiva histórica 7o s 8o s 9o s 2ooo s 2oo9 CMF antraciclinas taxanos capecitabina

5 Tratamiento Adyuvante del Cáncer C de Mama: Perspectiva histórica 70s 80s CMF 90s 2000s EBCTCG, Lancet. 2005;365:1687,2005.

6 Tratamiento Adyuvante del Cáncer C de Mama: Perspectiva histórica 70s 80s 90s CMF Anthras 2000s EBCTCG, Lancet. 1998;352:930.

7 Pros y contras de las antraciclines vs CMF como terapia adyuvante del cáncer de mama Pros: más eficaz que CMF Aumento absoluto de supervivencia a 10 años de 3-4%

8 Pros y contras de las antraciclines vs CMF como terapia adyuvante del cáncer de mama Pros: más eficaz que CMF Aumento absoluto de supervivencia a 10 años de 4% Contras: toxicidades graves irreversibles Miocardiopatía dilatada (aguda 1-2%, retardada?)

9 Type I and Type II Treatment-Related Cardiotoxicity Type I Anthracycles can cause a chronic, irreversible cardiomyopathy Cumulative-dose related Irreversible (cell death) Myocardial structural changes and cardiac tissue remodeling Typical biopsy changes Type II Not cumulative-dose related Largely reversible (cell dysfunction) Absence of anthracycline-like biopsy changes Trastuzumab is the model

10 Cardiac Toxicity of Anthracyclines Damage starts with the first administration seldom noted at low cumulative dosages because of cardiac reserves Study Regimen Cardiac Toxicity BCIRG 001 FAC x 6 TAC x 6 PASC 01 FEC 100 x 6 FEC 100 x 6 D US AC x 4 TC x 4 0.7% 1.6% 1.3% 0.4% 1% 0.5% CALGB 9741 A C T q3w A C T q2w Less than 6-year follow-up 2.5% 1.3%

11 Cardiac Toxicity of Anthracyclines Damage starts with the first administration seldom noted at low cumulative dosages because of cardiac reserves but subclinical damage, allowing later insult or sequential stress to trigger cardiac dysfunction Cardiomyopathy may present months or years after chemotherapy (sequential stress or injury may explain some late cardiotoxicity)

12 Women aged 66 to 70 years: freedom from congestive heart failure (CHF) by adjuvant chemotherapy type Pinder, M. C. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

13 Survival According to the Underlying Cause of Cardiomyopathy Proportion of Patients Surviving Due to doxorubicin Due to infiltrative myocardial disease Peripartum Idiopathic Due to ischemic heart disease Due to HIV infection Years Felker GM, et al. N Engl J Med. 2000;342:

14 Pros y contras de las antraciclines vs CMF como terapia adyuvante del cáncer de mama Pros: más eficaz que CMF Aumento absoluto de supervivencia a 10 años de 4% Contras: toxicidades graves irreversibles Miocardiopatía dilatada (aguda 1-2%, tardía? Riesgo extra de leucemias (0.5%)

15 Adjuvant Chemotherapy of Breast Cancer: Historical Perspective 70s 80s CMF Anthras Study CALGB 9344 (1) NSABP B-28 (2) GEICAM 9906 (3) Patients (N) Control Arm Experimental Arm Media FU (mo.) 3121 ACx4 ACx4 Px ACx4 ACx4 Px FECx6 FECx4 wpx s 2000s Taxanes BCIRG 001 (4) ECOG 2197 (5) USO 9735 (6) PACS 01 (7) 1491 FACx6 TACx ACx4 ATx ACx4 TCx FECx6 FECx4 Dx3 60 TAXIT 216 (8) 972 Ex4 CMFx4 Ex4 Tx4 CMFx4 53 BIG 2-98 (9) 2887 Ax4 CMFx4 ACx4 CMFx4 Ax3 Tx3 CMFx3 ATx4 CMFx Henderson et al. J Clin Oncol. 2003;21: Mamounas et al. J Clin Oncol. 2005; 23: Rodriguez-Lescure et al. ASCO 2007; Abstract Martin et al. N Engl J Med. 2005;352: Goldstein et al. ASCO 2005; Abstract Jones et al. J Clin Oncol. 2006;24: Roché et. al. J Clin Oncol. 2006; 24: Bianco et al. ASCO 2006; Abstract LBA Crown et al. ASCO 2006; Abstract LBA519.

16 BCIRG 001: Study design Martin, M. et al. N Engl J Med 2005;352:

17 BCIRG 001: Survival Rates in the Two Study Groups Martin, M. et al. N Engl J Med 2005;352:

18 Molecular Predictors of Efficacy of Adjuvant Weekly Paclitaxel in Early Breast Cancer R F E C F E C 600 mg/m 2 90 mg/m mg/m 2 q3w Paclitaxel 100 mg/m 2 Weekly Martin M et al, Breast Cancer Res Treat, in press, 2009

19 US Oncology 9735: Study Design 4 x TC q3w Taxotere (75 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) R n=506 N= % ER+ 38% N 4 x AC q3w Doxorubicin (60 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) n=510 Eligibility: Stage I, II, or III disease Tamoxifen was given to all ER+ patients Median follow up: 5.5 years Jones, S. E. et al. J Clin Oncol; 24:

20 US0 9735: (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment; (D) OS by treatment and age Copyright American Society of Clinical Oncology Jones, S. et al. J Clin Oncol; 27:

21 GEICAM 9805: Pure N- study

22 TAC Produces Significant DFS Benefit Regardless of Nodal Status BCIRG 001 Node Positive Median follow up: 55 months GEICAM 9805 High risk, Node Negative Median follow up: 67 months 1.0 TAC 75% 1.0 TAC 91% Cumulative probability FAC 68% Cumulative probability FAC 86% 0.2 HR=0.72 [95% CI, ] Stratified log rank p= HR=0.67 [95% CI, ] Stratified log rank p= Time (months) Time (months) Martín M et al. N Engl J Med. 2005;352: ; Martin M et al. Proc ASCO. 2008;26(No 15S):16s. Abstract 542.

23 PACS 01: Study design Roche, H. et al. J Clin Oncol; 24:

24 PACS 01: SLE (A) y SG (B) B Roche, H. et al. J Clin Oncol; 24:

25 Quimioterapia Adyuvante del CM: Evolución 100% SUPERVIVENCIA LIBRE DE ENFERMEDAD 50% 75% TAC 67% AC-Taxol FAC CMF Cirugia 35,9% 32,4% Pacientes con Ganglios Positivos 26% 0% añosa Bonadonna, 1992; EBCTG, 2000; Citron, JCO 2003; Martin, NEJM 2005;

26 Quimioterapia Adyuvante del CM Evolución SUPERVIVENCIA LIBRE DE ENFERMEDAD 100% 50% 75% 67% TAC AC-Taxol FAC CMF Cirugia 35,9% 32,4% 26% 0% años Bonadonna, 1992; EBCTG, 2000; Citron, JCO 2003; Martin, NEJM 2005;

27 Breast Cancer: 5-Year Survival by No. of Involved Axillary Lymph Nodes 80% 60% 5-year survival 40% 20% 0% >20 No. of axillary lymph nodes Harris J et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557.

28 Predicción clásica del riesgo de recurrencia St Gallen, 2007 LOW RISK N0 and all the following: pt 2 cm Grade 1 No extensive peritumoral vascular invasion ER or PR + HER2/neu Age 35 years Adjuvant Online A program for aiding health professionals in making estimates of outcome of patients with invasive cancer who have undergone definitive local therapy (without prior radiation or systemic therapy) and who are now deciding on whether to get systemic adjuvant therapy INTERMEDIATE RISK N0 and one of the following: pt > 2 cm Grade 2-3 Extensive Peritumoral vascular invasion ER and PR absent HER2/neu + Age < 35 years N+ (1-3 nodes) and one of the following: ER and PR absent HER2/neu HIGH RISK N+ (1-3 nodes) and: ER and PR absent or HER2/neu + N+ ( 4 nodes) Goldhirsch A et al. Ann Oncol. 2007;18:

29 One dumb tumor is still smarter than 10 smart oncologists Un tumor tonto es aun más listo que 10 oncólogos listos George Sledge

30 Las nuevas tecnologías han cambiado nuestra concepción n del cáncer c de mama Siglo XIX 1980s 2000 Siglo XXI DNA arrays SNP analysis Multiplex PCR RH FISH Proteómica Histologia Genes aislados Múltiples genes

31 Progress in the Adjuvant Treatment of Breast Cancer XX Century Empirical Oncology XXI Century Molecular/Genomic Oncology FOCUS ON: DISEASE STAGE (TNM) TUMOR BIOLOGY RISK ESTIMATION: BASED ON TNM TNM-MOLECULAR FACTORS TREATMENT: ONE SIZE FITS ALL TAILORED TREATMENT CONCEPT: A SINGLE DISEASE A FAMILY OF DISEASES

32 Gene-Expression Signatures as Predictors of Relapse in Early Breast Cancer Van de Vijver M et al. N Engl J Med. 2002;347:1999. Paik et al. N Engl J Med. 2004;351:2817.

33 Microarrays de cdna: perfil genético vs perfil clínico Microarray St Gallen SLE SLE 40% buen pronóstico 60 % mal pronóstico <15% bajo riesgo 85% intermedio/alto riesgo van de Vijver et al, NEJM 2002; 347: PERFIL GENÉTICO: mayor sensibilidad y especificidad

34 Quimioterapia (QT) adyuvante del CM: Aspectos clave Selección de pacientes para QT basado en riesgo de recaída sin QT basado en pronóstico genómico Selección del esquema de QT para un paciente individual: mejor fármaco/régimen ( QT individualizada?) toxicidad aguda y crónica del régimen enfermedades concomitantes y expectativa de vida del paciente

35 Gene-Expression Signatures as Predictors of Relapse in Early Breast Cancer Paik et al. N Engl J Med. 2004;351:2817.

36 Anthracyclines: The First Generation of CytotoxicTargeted Agents? A Possible Dream Di Leo A, et al; JCO 23:5011,2008

37 Anthracyclines vs CMF and her2 status: DFS Gennari, A. et al. J. Natl. Cancer Inst :14-20

38 NCIC-MA5: Study Design NCIC-MA.5 Premenopausal node positive (N = 710) CMF 6 cycles every 4 weeks Cyclophosphamide 100 mg/m 2 PO x 14 days Methotrexate 40 mg/m 2 IV Days 1, 8 5-FU 600 mg/m 2 IV Days 1, 8 CEF 6 cycles every 4 weeks Cyclophosphamide 75 mg/m 2 PO x 14 days Epirubicin 60 mg/m 2 IV Days 1, 8 5-FU 500 mg/m 2 IV Days 1, 8 Cotrimoxazole or Norfloxacin/ Ciprofloxacin Levine MN, et al. J Clin Oncol. 2005;23:

39 NCIC-MA5: 100 Patients (%) P =.047 CEF CMF Yrs No. at CEF Risk: CMF Reprinted with permission American Society of Clinical Oncology. All rights reserved. Levine MN, et al. J Clin Oncol. 2005;23:

40 Supervivencia global (CEF vs CMF) de acuerdo con el estado de TOP2A (A: anormal; B: normal) en el estudio MA.5 O'Malley, F. P. et al. J. Natl. Cancer Inst. 2009

41 Toponomía de los genes de HER2 y TOPO II 17 q q q 21.2 Normal Deletion Amplified Slamon D et al, SABCS 2008 HER2 Core region TOPO II region

42 Estrogen receptor expression and efficacy of Docetaxel in Early Breast Cancer: A Pooled Analysis of 3490 Patients Included in Two Randomized Trials F. Andre, K. Broglio, H. Roche, M. Martin, J. MacKey, F. Penault-Lorca, G. N. Hortobagyi, D. A. Berry, L. Pusztai

43 Aumento de supervivencia a 5 años con docetaxel de acuerdo con el nivel de expresión de RE Beneficio absoluto en SG a 5 años RE negativo 10.5% RE moderadamente positivo 4.5% RE intensamente positivo 4.8%

44 Molecular portraits of human breast tumors The intrinsic subtype classification Perou CM et al, Nature 406:747,2000

45 BCIRG 001: Clasificación genómica Basada en un panel IHQ Luminal A: HR+, HER2-, Ki67 low Luminal B: HR+, KI67 high or HER2+ HER2: HER2+, ER Triple Negative: ER, PR, and HER2 Hugh, J. et al. J Clin Oncol; 27:

46 BCIRG 001: SLE en las pacientes tratados con FAC ( ) o TAC ( ) de acuerdo con el subtipo biologico Hugh, J. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

47 Molecular Predictors of Efficacy of Adjuvant Weekly Paclitaxel in Early Breast Cancer (GEICAM 9906) R F E C F E 600 mg/m 2 90 mg/m mg/m 2 q3w Paclitaxel Samples were clasified as: Luminal A: HR+, HER2-, Ki67 low Luminal B: HR+, KI67 high or HER2+ HER2: HER2+, ER Triple Negative: ER, PR, and HER2 Basal-like: TN plus either CK 5/6+ or EGFR+ C 100 mg/m 2 Weekly Martin M et al, Breast Cancer Res Treat, in press, 2009

48 Molecular Predictors of Efficacy of Adjuvant Weekly Paclitaxel in Early Breast Cancer GEICAM 9906 Martin M et al, Breast Cancer Res Treat, in press, 2009

49 Conclusiones La quimioterapia adyuvante aumenta la supervivencia en tumores tanto RH+ como RH A quién tratar?: las plataformas genómicas (Mammoprint, Oncotype Dx) podrían permitir una mejor selección de enfermas candidatas a recibir quimioterapia Con qué regímenes?: las antraciclinas parecen más efectivas que terapias menos tóxicas sólo en enfermas cuyos tumores tienen alteraciones de los genes de HER2 (o topoiialfa?) los taxanos parecen especialmente eficaces en tumores triple negativo