Neoadyuvancia en Cáncer de Mama. E. Ciruelos Servicio de Oncología Médica Hospital 12 de Octubre

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2 Neoadyuvancia en Cáncer de Mama E. Ciruelos Servicio de Oncología Médica Hospital 12 de Octubre

3 Justificación - Excelentes tasas de respuestas en CM localmente avanzado e inflamatorio (tratamiento estándar) Chia S, JCO 2008; 26: 786 Tasa alta de respuesta clínica (60-70%) Tasa baja de respuesta patológica (20%) - Mayor tasa de cirugía conservadora (resultado estético) - Supervivencia equivalente a la quimioterapia adyuvante (SLE, SG)

4 Tratamiento neoadyuvante del cáncer de mama VENTAJAS Inicio precoz del tto sistémico Downstaging (operabilidad, qx conservadora) Test in vivo del efecto antitumoral Valor pronóstico de pcr* Oportunidad de marcadores surrogados Desarrollo nuevos fármacos

5 Tratamiento neoadyuvante del cáncer de mama DESVENTAJAS Diagnóstico inicial según biopsia/cilindro (no refleja heterogeneidad del tumor) No estadiaje histopatológico Riesgo de enfermedad multifocal residual Requiere Unidad Multidisciplinar

6 EBCTCG, Sept 2006 Mieog JS, Cochrane Database Syst Rev 2007; CD005002

7 Tipos de Marcadores Subrogados del Tratamiento Neoadyuvante Diagnostico Neoadyuvancia Cirugía Marcadores Tempranos -Ki 67 -Imagen -Otros Marcadores Tardíos -PEPI score -RCp -Enf Residual

8 NSABP B-18 Operable breast cancer (n 1523) Randomization Surgery AC x 4 AC x 4 Surgery pcr 13% Fisher B, J Clin Oncol 1998; 16: Wolmark N, J Natl Cancer Inst 2001;

9 NSABP B años seguimiento Rastogi P, J Clin Oncol 2008; 26:

10 NSABP B-18 Rastogi P, J Clin Oncol 2008; 26:

11 NSABP B-27 Operable breast cancer Randomization n=784 n=777 n=783 AC x 4 AC x 4 AC x 4 AC 60/600/m 2 Tam 20mg/day x 5yr Taxotere 100mg/m 2 Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4 I II III Bear HD, J Clin Oncol 2006; 24:

12 NSABP B-27: pathological complete responses in breast 30% 25% 20% 26.1%* 7.2 DCIS only No tumor 15% 12.8%* 14.3%* 10% % % Group I (n=764) Group II (n=767) Group III (n=775) Bear HD, J Clin Oncol 2006; 24:

13 NSABP B-27: OS, DFS, RFS 16 años seguimiento Rastogi P, J Clin Oncol 2008; 26:

14 NSABP B-27: overall survival pcr vs non-pcr patients Rastogi P, J Clin Oncol 2008; 26:

15 Definiciones de pcr Ausencia de tumor invasivo en mama (NSABP) Ausencia de tumor invasivo en mama y axila (MDA) Ausencia de tumor invasivo y no invasivo en mama y axila (GBG) Symmans (MDA; GEICAM)

16 Von Minckwitz, JCO 2012

17 CTNeoBC Selected Trials 12 neoadjuvant randomized controlled trials pcr clearly defined with all necessary data collected Long-term follow-up EFS and OS data collected GBG: 7 trials 6243 NSABP: 2 trials 3171 EORTC: 1 trial 1856 ITA: 2 trials 685 Total # patients GBG, NSABP, AGO-B, EORTC, BIG, Fondazione Michelangelo, SweBCG, UNC, NCI, FDA FDA, SABCS 2012

18 Considerations FDA For Future Trials: pcr Definition A pcr definition that includes the assessment of the axillary nodes (ypt0ypn0 or ypt0/isypn0) should be used in future trials.

19 FDA, SABCS 2012 Association of pcr with EFS and OS HR=0.48, P* < HR=0.36, P* < pcr=ypt0/is ypn0 * Nominal p-value

20 Sorlie, T et al. PNAS, 2001 Perou, CM et al. Nature, 2000 Perreard, L et al. Breast Cancer Res, 2006 Molecular classification in breast cancer: The intrinsec subtypes

21 N 6377 Von Minckwitz, JCO 2012

22 Luminal A Luminal B HER2 - Luminal B HER2+ HER2+ RE- TN Von Minckwitz, JCO 2012

23 FDA, SABCS 2012 Association of pcr with EFS in HR+ HER2-SubtypeHR+ HER2- Subtype HR=0.49, P* < HR=0.63, P* = 0.07 HR=0.27, P* < pcr=ypt0/is ypn0 * Nominal p-value

24 FDA, SABCS 2012 Association of pcr with EFS in Her2-positive Subtype HR=0.39, P* < HR=0.58, P* = HR=0.25, P* < pcr=ypt0/is ypn0 * Nominal p-value

25 Association of pcr with EFS in Triple Negative Subtype HR=0.24, P* < pcr=ypt0/is ypn0 FDA, SABCS 2012 * Nominal p- value

26 Breast Cancer Intrinsic Subtypes: A Spectrum Endocrine Dependent Chemo Resistant Endocrine Independent Chemo Sensitive Lum A Lum B HER2-rich Basal-like Others Path ways ER HER Family Prolif n Survival ER HER Prolif n Survival Family Hayes D J. Clin. Oncol ;

27 pcr Rates by Tumor Subtypes Grade 1-2 Grade 3 HR+ No Tras Yes Tras HER2+ HR+ No Tras Yes Tras HER2+ HR- TRIPLE NEG FDA, SABCS 2012

28 Probability of pcr Higher OncotypeDX Recurrence Score Associated with Higher Likelihood of pcr 100% 90% 80% 70% 60% 50% Low risk Int. risk High risk 40% 30% 20% 10% 0% Recurrence Score Gianni L et al., JCO 2005

29 HER2+

30 MDA Operable breast cancer HER2+, n T x 12 > FEC + Trastuzumab/s FEC > Taxol x 12 + Trastu Surgery Surgery pcr breast 56% 54% pcr breast+nod es 48% 46% pcr si ER- 72% 76% Buzdar AU, ASCO 2013

31 NOAH study design (n=115) H + AT q3w x 3 cycles HER2-positive LABC (IHC 3+ or FISH+) HER2-negative LABC (IHC 0/1+) (n=113 (n=99) ) AT AT q3w x 3 cycles q3w x 3 cycles H + T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles Surgery followed by radiotherapy a T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a H continued q3w 19 crossed over to H to week 52 IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); q3w, every 3 weeks; T, paclitaxel (175 mg/m 2 ); q4w, every 4 weeks a Hormone receptor-positive patients will receive adjuvant tamoxifen

32 pcr breast (+ nodes) rates in the NOAH trial Patients (%) % (38%) p=0.002 p= % (19%) 16% 0 With H Without H HER2 negative HER2 positive pcr Gianni, Lancet 2010

33 DFS and OS: HER2-positive population DFS - HR 0,64 (p 0,01) a favor de trastuzumab OS - HR 0,66 (p 0,05) a favor de trastuzumab DFS en pcr: HR 0,29 DFS en no pcr: HR 0.92 Median follow-up is 5,4 years Gianni, ASCO 2013

34 N 217 E 90 C 600 x 4 Paclitaxel Trastu 6 mg/kg x 4 Cirugía Trastu x 1 año pcr: ypt0 38,7% ypt0n0 22,6%

35 N 217 E 90 C 600 x 4 Paclitaxel Trastu 6 mg/kg x 4 Cirugía Trastu x 1 año pcr: ypt0 38,7% ypt0n0 22,6%

36 HER2+: Doble bloqueo

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39 5 FU 600 mg/m 2 Epi 75 mg/m 2 CTX 600 mg/m 2 Paclitaxel 80 mg/m 2 Trastuzumab 2 mg/kg R A N D O M I Z A T I O N Lapatinib 1000 mg CDD Lapatinib 1500 mg continuous daily dose (CDD) C O R E B I O P S Y S U R G E R Y A B C LVEF CHERLOB trial (Guarnieri V, ASCO 2011)

40 Y NeoSphere: study design Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel + trastuzumab THP (n=107) docetaxel + trastuzumab + pertuzumab HP (n=107) trastuzumab + pertuzumab TP (n=96) docetaxel + pertuzumab S U R G Study dosing: q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 17 docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 21 BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=t2 3, N2 3, M0 or T4a c, any N, M0; operable=t2 3, N0 1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel 3 R

41 NeoAltto Neosphere GeparQuinto Pac-L Pac-H Pac- HL Doc-H Doc- HP HP Doc-P ED H ED L pcr B 24,7% 29,5% 51,3% 29% 45,8% 16,8% 24% 50,4% 35,2% pcr B+N 20% 27,6% 46,9% 21,5% 39,3% 11,2% 17,7% 45% 29,9% pcr RE- 33,8% 36,5% 61,3% 36,8% 63,2% 29,1% 30% - -

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43 pcr, % 95% CI NeoSphere: pcr and hormone 70 receptors status ER or PR pos ER and PR neg TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel 7

44 HER2+: Doble bloqueo Opción sin antraciclinas

45 Tryphaena (Schneeweiss, SABCS 2011) Cycles A FEC Docetaxel HER2-positive EBC entrally confirmed (n = 225) B C Pertuzumab + trastuzumab FEC Docetaxel Docetaxel Pertuzumab + trastuzumab Pertuzumab + trastuzumab S u r g e r y Trastuzumab to complete 1 year Carboplatin All 3 arms were experimental Study dosing q3w: FEC: 500 mg/m 2, 100 mg/m 2, 600 mg/m 2 Carboplatin: AUC 6 Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Pertuzumab: 840 mg loading dose, 420 mg maintenance Docetaxel: 75 mg/m 2 (escalating to 100 mg/m 2 if tolerated, in Arms A and B only)

46 Pathologic complete response (%) Pathologic complete response by hormone receptor status ER- and PR-negative 79.4 ER- and/or PR-positive 83.8 ypt0/is FEC+H+P x3 T+H+P x3 (n = 73) FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; PR, progesterone receptor; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

47 Neoadyuvancia en HER2+ Doble bloqueo HER2 + QT (excepto B41) Antraciclinas excepto en casos seleccionados (Tryphaena) Reexplorar la combinación antiher2 + HT (Pamela) Relevancia de pcr como marcador surrogado?

48 Neoaltto: no diferencias en DFS y OS Piccart M, SABCS 2013

49 Fenotipo Triple Negativo

50 pcr Rates by Tumor Subtypes Grade 1-2 Grade 3 HR+ No Tras Yes Tras HER2+ HR+ No Tras Yes Tras HER2+ HR- TRIPLE NEG FDA, SABCS 2012

51 Identification of Human TNBC Subtypes Basal-like 1: cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) Lehmann, Bauer, Chen, et al., J Clin Invest doi: /jci LAR: Androgen receptor and downstream genes, luminal features

52 GEPARSIXTO (von Minckwitz, ASCO 2013) Adición de carbo a tto neoadyuvante en TN y HER2+ pcr 46 vs 37% en global 58 vs 38% en TN (< 0,05) 33 vs 36 % en HER2+ (ns) en TN, si pt0/is N0, pcr de 64% (la mayor reportada en TN) Apoya estudios futuros con platinos en neoadyuvancia

53 CALGB (Sikov, SABCS 2013) Adición de carbo y bevacizumab a tto neoadyuvante en TN Paclitaxel semanal +/-beva +/- carboplatino seguido ACX4 (dd) pcr mama y axila: - 41 vs 54% a favor de carboplatino (p 0,0029) - 44 vs 52% tendencia a favor de beva (NS) Junto a datos de Geparsixto, valorar adición de carboplatino Necesario mayor seguimiento (SLE)

54 DNA Repair and synthetic lethality Chemo, XRT and Other Insults DNA DAMAGE Normal cell BRCA loss PARP deficient BRCA loss + PARP deficient HR BER HR BER HR BER HR BER VIABLE VIABLE VIABLE DEAD HR: Homologous Recombination BER: Base Excision Repair Adapted from Carey L. Oncologist 2010

55 DNA Repair and synthetic lethality Chemo, XRT and Other Insults DNA DAMAGE Normal cell BRCA loss PARP deficient X BRCA loss + PARP deficient HR BER HR BER HR BER HR BER VIABLE VIABLE VIABLE DEAD HR: Homologous Recombination BER: Base Excision Repair Adapted from Carey L. Oncologist 2010

56 DNA Repair and synthetic lethality Chemo, XRT and Other Insults DNA DAMAGE Normal cell BRCA loss PARP deficient X BRCA loss + PARP deficient HR BER HR BER HR BER HR BER X VIABLE VIABLE VIABLE DEAD HR: Homologous Recombination BER: Base Excision Repair Adapted from Carey L. Oncologist 2010

57 DNA Repair and synthetic lethality Chemo, XRT and Other Insults DNA DAMAGE Normal cell BRCA loss PARP deficient BRCA loss + PARP deficient X X X X HR BER HR BER HR BER HR BER VIABLE VIABLE VIABLE DEAD HR: Homologous Recombination BER: Base Excision Repair Adapted from Carey L. Oncologist 2010

58 DNA Repair and synthetic lethality Chemo, XRT and Other Insults DNA DAMAGE Normal cell BRCA loss PARP deficient BRCA loss + PARP deficient X X X X HR BER HR BER HR BER HR BER VIABLE VIABLE VIABLE DEAD HR: Homologous Recombination BER: Base Excision Repair Synthetic Lethality That which does not kill you sets you up so that the next blow will be lethal Adapted from Carey L. Oncologist 2010

59 PRECOG 0105: (ML Telli, ASCO 2013) Neoadyuvancia fase II gem y carbo y iniparib en TN y BRCA ½ mutados I-IIIA, T> 1cm. TN o mutación BRCA ½ Carbo AUC2 d1,8 + Gem 1000 d1,8 + iniparib 5,6 mg (x4) cada 3sem, x 6 ciclos N80 pcr pcr 36% en global 33% si BRCAwt 47% si BRCA mut 56% si TN y BRCA mut PAM50 subtipos :Subtipo inmunomodulador con 79% de pcr

60 Fenotipo Triple Negativo Quimioterapia convencional basada en antraciclinas y taxanos Posible papel para platinos e inhibidores de PARP Subtipos intrínsecos (7) Papel dudoso de bevacizumab

61 Tratamiento hormonal neoadyuvante

62 Tratamiento endocrino neoadyuvante cáncer de mama (CM) - pcr poco habitual (< 10%) - Respuestas clínicas frecuentes, más cirugía conservadora - Duración indeterminada (>16 semanas; respuestas 12-24m) - Descenso de Ki67: marcador pronóstico a largo plazo (estudio IMPACT, Dowsett M, J Natl Cancer Inst 2007; 99: ) - Ensayo clínico / No candidatas a QT neoadyuvante (postmenopaúsicas, edad, comorbilidad asociada)

63 ACOSOG Z-1031 Ellis M, SABCS 2010

64 Tratamiento hormonal adyuvante vs neoadyuvante Estudio adyuvante Resultados Estudio neoadyuvante Resultados BIG 1-98 Thurlimann 2005 Let > Tam N 8010 P024 Ellis 2003 Let > Tam N 185 ATAC Baum 2002 Ana > Tam N 9366 IMPACT Dowsett 2005 Ana > Tam N 147 MA 27 Goss 2010 Ana = Exe N 9000 Z1031 Ellis 2010 Ana = Exe N 165 FACE? Ana vs Let? N 4000 Z1031 Ellis 2010 Ana = Let N 161 Ellis M, SABCS 2010

65 Hormonoterapia Neoadyuvante Información Pronóstica PEPI Score Preoperative Endocrine Prognostic Index Basado en pt, N, ER score, y Ki-67 tras 3-4 meses de Tto Ellis MJ, et al. JNCI 2008

66 Aspectos de manejo

67 Neoadjuvant chemotherapy: How to optimize locoregional tx? Careful physical and radiological examination at diagnosis - measuring of primary tumor size - bilateral mammography, US, MRI - core needle biopsy in all suspected lesions - radiopaque clips placed within all lesions at biopsy - careful assessment of regional lymph nodes: - Physical exam - US +/- FNA - consider sentinel node biopsy before / after tx Symmans WF, J Clin Oncol 2007; 25:

68 Necesidad de trabajar en Unidades Multidisciplinares

69 Aspectos regulatorios

70 FDA: Aprobación Acelerada en base a RCp META-ANALISIS EN JUNIO 2012 RESULTADOS MA EN DIC 2012 GUIA DISEÑO EC APROB ACELERADA NEOADJUVANT TRIAL PATHOLOGIC AL COMPLETE RESPONSE pcr EFS OS ACCELERATED APPROVAL (pertuzumab) REGULAR APPROVAL

71 FDA pooled-analysis could not establish pcr as a surrogate endpoint for EFS/OS Possibly due to: low pcr rates small pcr improvements heterogeneous population lack of targeted therapies Larger pcr differences between treatment arms may translate into long-term outcome and may vary according to breast cancer subtype (more agressive.: TN, HER2+)

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