TRATAMIENTO PRECOZ ESTRATEGIAS CON TERAPIAS BIOLÓGICAS

1. TRATAMIENTO PRECOZ ESTRATEGIAS CON TERAPIAS BIOLÓGICAS Miquel Àngel Seguí Palmer

2. ESTRATEGIAS CON TERAPIAS BIOLÓGICAS Tratamientos orientados a una diana molecular diferenciada como es el Her2 (Trastuzumab y Lapatinib) Tratamientos sin un claro grupo de pacientes con una diana específica (Bevacizumab y ácido Zoledrónico) Tratamientos que ya tienen un peso específico y están integrados en la práctica habitual (Trastuzumab) Tratamientos que tienen algunos resultados prometedores en estudios de adyuvancia (ácido Zoledrónico) pero todavía precisan de más información . Tratamientos que están en fase de estudio y a la los que todavía les queda un largo recorrido antes de formar parte de las estrategias habituales en adyuvancia (Lapatinib y Bevacizumab).

3. TRASTUZUMAB

4. TRASTUZUMAB Indicación del fármaco en los tumores de teórico buen pronóstico

5. TRASTUZUMAB Cuando se analiza lo que pasa en el “mundo real”, aproximadamente la mitad de las pacientes Her2 + no reciben tratamiento adyuvante con Trastuzumab

6. TRASTUZUMAB

7. TRASTUZUMAB A retrospective cohort of 367, grade 1 or 2, node negative patients was analysed to assess the impact of HER2 status (Herceptest 3+ or FISH positive) on survival in this otherwise very good prognostic group. The patients were diagnosed between 1980- 2002, had full follow-up and were 89% ER positive, with 72% smaller than 20mm. 10% received chemotherapy and 91% received endocrine therapy.

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9. TRASTUZUMAB

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11. TRASTUZUMAB Recurrence Free Survival by HER2 Status Recurrence Free Survival by breast cancer subtype

12. TRASTUZUMAB Multivariable Models Conclusions • HER2 positivity is a powerful negative prognostic factor for patients with tumors 1 cm or less (HR: 2.7, 95% CI 1.44-5.0). • Systemic treatment with anti-HER2 directed therapies should be strongly considered in this population. • Clinical trials should include this group of patients.

13. TRASTUZUMAB Datos de cardiotoxicidad de una serie de 54 pacientes Her2+ tratadas con trastuzumab fuera de un ensayo clínico

14. TRASTUZUMAB Twelve patients (22.2%) interrupted their trastuzumab therapy. Eleven (20.4%) due to an asymptomatic drop in LVEF of >10% while one patient (1.9%) experienced a symptomatic cardiac toxicity requiring treatment. The mean number of cycles completed prior to discontinuation was 2.75 and the mean drop in LVEF was 17.6%. Two patients restarted and completed their trastuzumab therapy at a later date. • Significant decline in LVEF after 12 weeks on trastuzumab (p = 0.003) • LVEF values remained stable thereafter

15. TRASTUZUMAB Datos preliminares de toxicidad de un estudio fase II de gran tamaño con el esquema TC con trastuzumab concomitante en pacientes Her2+

16. TRASTUZUMAB

17. ÁCIDO ZOLEDRÓNICO ABCSG - 12

18. ÁCIDO ZOLEDRÓNICO

19. ÁCIDO ZOLEDRÓNICO

20. ÁCIDO ZOLEDRÓNICO The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST H. Eidtmann, N.Bundred, R. De Boer, A. Llombart, N. Davidson, P. Neven, G. von Minckwitz, J. Miller, N. Schenk, and R.Coleman on behalf of the ZO-FAST Trialists’ Group

21. ÁCIDO ZOLEDRÓNICO The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST H. Eidtmann, N.Bundred, R. De Boer, A. Llombart, N. Davidson, P. Neven, G. von Minckwitz, J. Miller, N. Schenk, and R.Coleman on behalf of the ZO-FAST Trialists’ Group

22. ÁCIDO ZOLEDRÓNICO The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST H. Eidtmann, N.Bundred, R. De Boer, A. Llombart, N. Davidson, P. Neven, G. von Minckwitz, J. Miller, N. Schenk, and R.Coleman on behalf of the ZO-FAST Trialists’ Group

23. ÁCIDO ZOLEDRÓNICO The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving letrozole: 36 months follow-up of ZO-FAST H. Eidtmann, N.Bundred, R. De Boer, A. Llombart, N. Davidson, P. Neven, G. von Minckwitz, J. Miller, N. Schenk, and R.Coleman on behalf of the ZO-FAST Trialists’ Group

24. ÁCIDO ZOLEDRÓNICO

25. ÁCIDO ZOLEDRÓNICO

26. LAPATINIB Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-positive breast cancer is not feasible due to excessive diarrhea: updated results. Dang C, Lin N, Moy B, Come S, Lake D, Theodoulou M, Troso-Sandoval T, Dickler M, Gorsky M, D'Andrea G, Modi S, Seidman A, Drullinsky P, Partridge A, Schapira L, Wulf G, Gilewski T, Atieh D, Mayer E, Isakoff S, Sugarman S, Fornier M, Traina T, Bromberg J, Currie V, Robson M, Burstein H, Overmoyer B, Ryan P, Kuter I, Younger J, Schumer S, Tung N, Zarwan C, Schnipper L, Chen C, Winer E, Norton L, Hudis C Memorial Sloan-Kettering Cancer Center, New York, NY; Dana Farber Cancer Institute, Boston, MA; Massachusetts General Hospital, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA From March 2007 to April 2008, we enrolled 95 pts. Median age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib

27. LAPATINIB 122 patients were accrued on this study . Adverse event data are available for 102 patients who initiated treatment (median cycles of treatment = 8 cycles)

28. LAPATINIB

29. BEVACIZUMAB

30. BEVACIZUMAB Tolerability ■ A total of 29 patients (21%) have discontinued study treatment; 16 patients discontinued due to adverse events. For those patients discontinuing treatment due to adverse events, an average of 7 cycles of treatment were administered. ■ Seven Grade 3/4 cardiac adverse events were observed. Documented CHF events reported in 3 patients: 1 in Arm A, and 2 in Arm B. All 3 patients discontinued study treatment at the time CHF was documented. ■ In Arm B, 1 patient died as a result of neutropenic sepsis with enterocolitis; 1 patient died of sepsis; 1 patient experienced prolonged hospitalization due to Typhlitis.

31. BEVACIZUMAB No new or unexpected safety findings have occurred compared with the safety profile reported for these three chemotherapy regimens without bevacizumab.

32. BEVACIZUMAB LVEF data for individual study patients over time Selected common adverse events.

33. BEVACIZUMAB Con un total de 158 casos entre ambos estudios, el 4-6% de las pacientes presentan disminución significativa de la FEVi durante este tratamiento, siendo anecdótica la aparición de toxicidad cardíaca con expresión clínica.

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37. RESUMEN TRASTUZUMAB No parece haber un subgrupo de pacientes Her2+ de “buen pronóstico”, por lo que siempre se debe considerar en estos casos la opción de un tratamiento adyuvante que incluya trastuzumab. Hasta un 20% de pacientes puede necesitar interrumpir el tratamiento con Trastuzumab por toxicidad cardiaca. El esquema TC + Trastuzumab tiene una mínima toxicidad cardiaca. Con toda seguridad esta estrategia de tratamiento va a ver incrementado su uso en pacientes frágiles o con riesgo cardíaco

38. RESUMEN ÁCIDO ZOLEDRÓNICO EN ADYUVANCIA Seguimos con claros datos que sugieren la utilidad de esta estrategia de tratamiento, pero sin duda necesitamos una confirmación en otros estudios (AZURE, SWOG 0307) que la conviertan en un tratamiento adyuvante razonable. LAPATINIB A causa de la diarrea, se recomienda reducir la dosis de Lapatinib de los 1000 mg/día a 750 mg/día cuando el tratamiento se administra concomitante con Trastuzumab y Paclitaxel. La toxicidad cardíaca es mínima.

39. RESUMEN BEVACIZUMAB Tres estudios demuestran la seguridad cardíaca de la combinación del bevacizumab en esquemas con antraciclinas y taxanos en programas de adyuvancia. Un estudio de tratamiento primario en pacientes con cáncer de mama operable con un esquema de tratamiento que incluye Bevacizumab muestra una RPc en mama y axila del 33%, superior a la habitual tasa de RPc del 15-20% conseguida en grupos de pacientes similares con esquemas basados en antraciclinas y taxanos

40. TRATAMIENTO PRECOZ ESTRATEGIAS CON TERAPIAS BIOLÓGICAS