10. Cáncer de Mama Avanzado
6-10%
Enfermedad
Metastásica
20-85%
Recurrencia
de Enf
Tempranas
Tratamiento
Paliativos
Piccart et al. The Oncologist 2004;9:617-632
Carlson et al. The Oncologist 2003;8:514-520
11.
12. Síntomas en Cáncer de Mama
Avanzado
Asintomática Tumor primario Dolor óseo
Tos / Disnea Déficit
neurológico
Otros
De Vita et al. Cancer Principles and Practice of Oncology 9th Edition. 2011
13. Tratamiento Sistémico Paliativo
Objetivos Primarios del Tratamiento
Mejorar la calidad de vida
Prevenir y paliar los síntomas
Prolongar la supervivencia
Beslija et al. Annals of Oncology 18: 215–225, 2007
15. Factores Asociados a la Paciente
• Expectativa
• Efectos secundarios
Preferencia de la paciente
• Comorbilidades
• Estado funcional
• Estado nutricional
Condición médica de la paciente
• Apoyo familiar
• Residencia
• Seguro de salud
Condición socio-económica de la paciente
ESMO Handbook of Advanced Cancer Care. 2006
16. Factores Pronósticos
Factor
Pronóstico
ECOG
Sitio de Met
# de Sitio de Met
Receptores Hormonales
HER2
Intérvalo Libre de Enfermedad
Terapia Adyuvante Previa
Terapia Previa para CMM
Favorable
Bueno
Tej Blando, Óseo
Oligo
Positivo
Negativo
> 2 años
No
No
Desfavorable
Pobre
Vísceras
Múltiples
Negativo
Positivo*
< 2 años
Sí
Sí
Beslija et al. Annals of Oncology 18: 215–225, 2007
20. Beneficios del Tratamiento Sistémico
• Respuesta Objetivas está Asociada a Mejoría de los Síntomas
Geels et al. J Clin Oncol 2000;18:2395-2405.
21. Caso Clínico #1
• Paciente femenina de 75 años.
• Comorbilidades: HTA, DM-2, Cardiopatía
isquémica hace 2 años
• Tumor de 7 cm, ulcerado en la mama
izquierda.
22. Caso Clínico #1
• Biopsia:
– Carcinoma ductal
infiltrante
– Grado 1
– RE (100%+)
– RP (50%+)
– HER2 (-)
23. Caso Clínico #1
• Opciones de tratamiento
– Referir a Cirugía para resección del tumor de
mama ulcerado.
– Referir a Oncología para tratamiento sistémico
paliativo.
– Referir a Cuidados Paliativos para mejor soporte
médico.
– Explicarle a la paciente que tiene enfermedad
terminal y ya no hay nada que ofrecerle.
32. Hormonoterapia – Conclusiones
• Tratamiento de elección en cáncer de mama
avanzado RH+ HER2-.
• Regular tasa de respuesta con buen perfil de
toxicidad.
• Utilizar todas las líneas de tratamientos
hormonales antes de iniciar QT.
33. Caso Clínico #2
• Paciente femenina de 35 años.
• Sin antecedentes personales de relevancia.
• Lesión de 5 cm en la mama derecha de rápido
crecimiento asociado a tos seca y disnea de
moderado esfuerzo.
34. Caso Clínico #2
• Biopsia de mama
– Carcinoma ductal
infiltrante
– Grado 3
– RE (0%+)
– RP (0%+)
– HER2 (-)
35. Caso Clínico #2
• Opciones de tratamiento
– Referir a Cirugía para resección del tumor de
mama de rápido crecimiento.
– Referir a Oncología para tratamiento sistémico
paliativo.
– Referir a Cuidados Paliativos para mejor soporte
médico.
– Explicarle a la paciente que tiene enfermedad
terminal y ya no hay nada que ofrecerle.
37. Tasa de Respuesta
Agente 1° Línea (%) 2° Línea (%) Post A/T (%)
Doxorrubicina 40-50 32-36 ---
Epirrubicina 52-68 25-35 ---
Paclitaxel 29-63 19-57 ---
Docetaxel 47-65 39-58 17
Capecitabina 20-30 20-27 20
Gemcitabina 23-37 13-41 22
Vinorelbine 40-44 17-36 25
Gralow et al. Breast Cancer Research and Treatment (2005) 89: S9–S15
38. • Monoterapia secuencial es la opción preferida
en enfermedad avanzada en la ausencia de
– Rápida progresión clínica
– Metástasis visceral que pone en peligro la vida del
paciente
– Necesidad de un control rápido de los síntomas o
la enfermedad
Cardoso et al. J Natl Cancer Inst 2009;101:1174–1181
39. La toma de la decisión óptima sobre continuar la QT debe
ser basado con discusiones entre el paciente y su médico.
Signos, síntomas, efectos adversos, calidad de vida y
preferencias debe ser monitoreada y tomada en cuenta.
Es razonable continuar la QT en ausencia de progresión o
efectos adversos significativos.
Pacientes con enfermedad estable o respuesta óptima puede
tomar descanso sin alterar el pronóstico a largo plazo.
Beslija et a.l Annals of Oncology 18: 215–225, 2007
40. Quimioterapia – Conclusiones
• Tratamiento de elección en cáncer de mama
avanzado RH negativos o cuando requiere
rápido control de la enfermedad.
• Monoterapia tiene mejor perfil de toxicidad
sin afectar la supervivencia comparado con
terapia de combinación.
41. Caso Clínico #3
• Paciente femenina de 54 años
• Antecedentes de HTA tratada con Lisinopril
• Consulta por cuadro de cefalea de fuerte
intensidad asociado a parestesia en MsIs
• Examen físico con lesión de 2 cm en el CSE de
la mama izquierda + adenopatía axilar
ipsilateral de 2 cm.
42. Caso Clínico #3
• Biopsia de mama:
– Carcinoma ductal
infiltrante
– Grado 3
– RE (2%+)
– RP (0%+)
– HER2 (3+)
43. Caso Clínico #3
• Opciones de tratamiento
– Referir a Radioncología para RT holocraneana.
– Referir a Oncología para tratamiento sistémico
paliativo.
– Referir a Cuidados Paliativos para mejor soporte
médico.
– Explicarle a la paciente que tiene enfermedad
terminal y ya no hay nada que ofrecerle.
46. Estudios Pivotes de Trastuzumab en
Cáncer de Mama Metastásico
1. Slamon DJ, et al. N Engl J Med. 2001;344:783-792. 2. Marty M, et al. J Clin Oncol. 2005;23:4265-4274.
Estudio
mOS (meses)
HR
(95% CI)
P
ValueQT Solo
QT +
Trastuzumab
Paclitaxel
(Slamon)[1] 20.3 25.1
0.80
(0.64-1.00)
.046
Docetaxel
(Marty)[2] 22.7 31.2
No
reportado
.0325
48. 1. Franklin MC, et al. Cancer Cell 2004; 5:317–328; 2. Junttila TT, et al. Cancer Cell 2010; 15:429–440;
3. Nahta R, et al. Cancer Res 2004; 64:2343–2346; 4. Scheuer W, et al. Cancer Res 2009; 69:9330–9336;
HER2HER1, 3, 4 Trastuzumab
Pertuzumab
• Pertuzumab binds to subdomain II and inhibits ligand-dependent signalling1
• Trastuzumab binds to subdomain IV and inhibits ligand-independent intracellular signalling2
• The pertuzumab–trastuzumab combination offers a more comprehensive HER2 blockade3,4
Pertuzumab
49. H, trastuzumab; HR, hazard ratio; P, pertuzumab;
PFS, progression-free survival; T, docetaxel
CLEOPATRA: Supervivencia Libre de
Progresión
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time (months)
PHT: median 18.5 months
HT: median 12.4 months
HR 0.62
95% CI = 0.51, 0.75
p < 0.001
∆ = 6.1 months
12.4 18.5
Independentlyassessed
PFS(%)
n at risk
402 345 267 139 83 32 10 0 0PHT
406 311 209 93 42 17 7 0 0HT
Baselga J, et al. N Engl J Med 2012; 366:109–119.
50. Stopping boundary for concluding statistical significance at this confirmatory, definitive analysis was p ≤ 0.0138
CI, confidence interval; H, trastuzumab; HR, hazard ratio; OS, overall survival;
P, pertuzumab; T, docetaxel
Swain SM, et al. SABCS 2012
(Abstract P5-18-26; poster presentation).
CLEOPATRA: Supervivencia Global
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
n at risk
0PHT
0HT
Time (months)
Overallsurvival(%)
45 50 55
0
0
9
4
33
22
84
67
143
128
230
198
317
285
342
324
371
350
387
383
402
406
89%
94%
1 year
2 years
69%
81% 3 years
66%
50%
PHT: 113 events; median not reached
HT: 154 events; median 37.6 months
HR 0.66
95% CI = 0.52, 0.84
p = 0.0008
52. Inhibición/Bloqueo de la
cascada de señalización
Señalización
intracelular
Mecanismo de Acción de T-DM1
T-DM1 se une a la proteína
Her2 de las células tumorales
El complejo receptor-
T-DM1 se internaliza
en el interior de la
célular tumoral Her2+
El inmunoconjugado
se degrada por la
acción del lisosoma,
dejando libre DM1, un
potente inhibidor de
microtúbulos, que
lleva a la célula a la
muerte por apoptosis
• A través de trastuzumab, T-DM1 se une al receptor
Her2 e inhibe la cascada de señalización
• Permite el aporte intracelular dirigido de DM1, un
potente agente antimicrotúbulo
53. EMILIA: Estudio Fase III
Supervivencia Libre de Progresión
Verma et al. N Engl J Med. 2012;367:1783-1791
54. EMILIA: Estudio Fase III
Eventos Adversos Grado 3 ≥2%
Verma et al. N Engl J Med. 2012;367:1783-1791
56. Caso Clínico #4
• Paciente femenina de 65 años.
• Antecedente de HTA, DM-2, Cardiopatía
dilatada y ECV isquémico hace 3 meses con
secuela de hemiplejía izquierda.
• Lesión de 5 cm en la mama izquierda con piel
de naranja asociado a dolor en la cadera y
brazo derecho.
57. Caso Clínico #4
• Biopsia de mama:
– Carcinoma ductal
infiltrante
– RE (0%+)
– RP (0%+)
– HER2 (-)
58. Caso Clínico #4
• Opciones de tratamiento
– Referir a Cirugía para resección del tumor de
mama con piel de naranja.
– Referir a Oncología para tratamiento sistémico
paliativo.
– Referir a Cuidados Paliativos para mejor soporte
médico.
– Explicarle a la paciente que tiene enfermedad
terminal y ya no hay nada que ofrecerle.
Breast cancer is the second most common cancer in the world and, by far, the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012 (25% of all cancers). It is the most common cancer in women both in more and less developed regions with slightly more cases in less developed (883,000 cases) than in more developed (794,000) regions. Incidence rates vary nearly four-fold across the world regions, with rates ranging from 27 per 100,000 in Middle Africa and Eastern Asia to 96 in Western Europe.Breast cancer ranks as the fifth cause of death from cancer overall (522,000 deaths) and while it is the most frequent cause of cancer death in women in less developed regions (324,000 deaths, 14.3% of total), it is now the second cause of cancer death in more developed regions (198,000 deaths, 15.4%) after lung cancer. The range in mortality rates between world regions is less than that for incidence because of the more favorable survival of breast cancer in (high-incidence) developed regions, with rates ranging from 6 per 100,000 in Eastern Asia to 20 per 100,000 in Western Africa.
Second consensus on medical treatment of metastatic breast cancer. Central European Cooperative Oncology Group CECOG
EORTC QLQ-C30
Case Report Form
The slide shows the primary endpoint of independently assessed PFS.
Very similar results were obtained in the investigator assessment of PFS, which also showed a significant improvement with PHT vs HT (HR 0.65; 95% CI = 0.54, 0.78; p < 0.001). Median investigator-assessed PFS was 18.5 months in the PHT group and 12.4 months in the HT group.
Reference
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366:109–119.
Reference
Swain SM, Kim S-B, Cortés J, et al. Confirmatory overall survival (OS) analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled Phase III study with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive first-line (1L) metastatic breast cancer (MBC). Cancer Res 2012; 72 (15 December suppl.): Abstract P5-18-26 (and associated poster presentation).
T-DM1 meets the requirements of the ideal ADC, as it is a customized, interdependent combination of a precisely targeted humanized mAb, a potent cytotoxic drug, and a stable linker that selectively kills cancer cells while minimizing effects on normal tissue.1–5
Trastuzumab is an ideal antibody partner for DM1.
First, the antigen to which it is directed, HER2, is selectively expressed on tumor tissue. HER2 is expressed at relatively low levels in normal adult tissues6 but is frequently overexpressed in various tumor types, including 20% to 25% of breast tumors.7
Second, when DM1 is conjugated to trastuzumab, trastuzumab retains its antitumor activities, such as antibody-dependent cell-mediated cytotoxicity (ADCC), inhibition of cell signaling through the PI3K/AKT pathway, and inhibition of HER2 shedding.8
DM1 is a highly potent cytotoxic drug that causes cell death by destabilizing microtubules.2,8
DM1 is conjugated to trastuzumab using a unique nonreducible thioether linker (SMCC, known as “MCC” once conjugated). This linker is more stable than traditional hydrazone or disulfide linkers, minimizing the possibility of linker failure resulting in systemic exposure to free DM1.2,9
As expected, there have been no clinical reports of linker failure.
References
1. Jaracz S et al. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043–5054.
2. Lewis Phillips GD et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290.
3. Wu AM et al. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137–1146.
4. Ricart AD et al. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245–255.
Junutula JR et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925–932.
Press MF et al. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5:953–962.
Slamon DJ et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182.
Junttila T et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2010. August 21 (E-pub ahead of print).
Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13:235–244.
T-DM1 has a combined proposed MOA: the biologic activity of trastuzumab1–11 and intracellular delivery of the potent cytotoxic agent DM1.12
Trastuzumab biological activity that is retained by T-DM1 includes flagging HER2-positive tumor cells for destruction via ADCC, constant HER2-receptor inhibition, and inhibition of HER2 shedding.13
It is hypothesized that after T-DM1 molecules bind to HER2, the receptor–ADC complex is internalized, T-DM1 is degraded in lysosomes, and DM1 is released into the cytoplasm, where it may subsequently inhibit microtubule assembly resulting in cell death.14
By exploiting the overexpression of HER2 receptors on tumor cells, T-DM1 is designed to preferentially deliver DM1 directly to HER2 overexpressed tumor cells, which may limit systemic adverse events.15
References
Hudziak RM et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9:1165–1172.
Lewis GD et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37:255–263.
Baselga J et al. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825–2831.
Hotaling TE et al. The humanized anti-HER2 antibody rhuMAb HER2 mediates antibody dependent cell-mediated cytotoxicity via FcγR II. Proc Am Assoc Cancer Res. 1996;37:471. Abstract 3215.
Pegram MD et al. Antibody dependent cell-mediated cytotoxicity in breast cancer patients in phase II clinical trials of a humanized anti-HER2 antibody. Proc Am Assoc Cancer Res. 1997;38:602. Abstract 4044.
Pegram M et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18:2241–2251.
Pegram MD et al. The molecular and cellular biology of HER2/neu gene amplification/over expression and the clinical development of Herceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res. 2000;103:57–75.
Merlin JL et al. In vitro comparative evaluation of trastuzumab (Herceptin®) combined with paclitaxel (TaxolTM) or docetaxel (TaxotereTM) in HER2-expressing human breast cancer cells. Ann Oncol. 2002;13:1743–1748.
Hirsch FR et al. Preclinical studies of gemcitabine and trastuzumab in breast and lung cancer cell lines. Clin Breast Cancer. 2002;3(Suppl 1):S12–S16.
Argiris A, DiGiovanna M. Synergistic interactions between tamoxifen and Herceptin®. Proc Am Assoc Cancer Res. 2000;41:718. Abstract 4565.
Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2009.
Parsons K et al. Trastuzumab directed cytotoxic therapy: efficacy against HER2- positive trastuzumab-insensitive breast cancer models and enhanced response in trastuzumab-sensitive models. AACR 2007. Abstract 649.
Junttila TT et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2010. August 21 (E-pub ahead of print).
Lewis Phillips GD et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290.
Niculescu-Duvaz I. Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer. Curr Opin Mol Ther. 2010;12:350–360.