Denosumab en el tratamiento del cáncer de...
Transcript of Denosumab en el tratamiento del cáncer de...
Denosumab en el tratamiento del cáncer de mama
Dr. José Ángel García Sáenz
Prevención de las complicaciones esqueléticas de las metástasis óseas
Como tratamiento adyuvante
Otros escenarios
TIPO DE TUMOR PACIENTES CON
METASTASIS OSEAS
Mieloma 95%
Mama 70%
Próstata 70%
Tiroides 60%
Vejiga 40%
Melanoma 40%
Pulmón 35%
Riñón 30%
Parkin & Coleman RE 2001
Mama
Radioterapia ósea
Fractura
Cirugía ósea
Compresión medular
Complicaciones esqueléticas
Lipton A 2000
43
52
11
3 4
34 34
4 4
33 37
25 22
2
8 5
Mieloma Próstata Pulmón
P
P
O
O
OH
OH
OH
OH
R1
R2
P
P
O
O
OH
OH
OH
OH
H2N
HO
P
P
O
O
OH
OH
OH
OH
N
HO
P
P
O
O
OH
OH
OH
OH
Cl
Cl
P
P
O
O
OH
OH
OH
OH
N
HO
N
ZOLEDRONICO n:377
PAMIDRONATO n:389
Ptes con >1 evento 46% 49% NS
Tº 1er evento 376 días 366 días NS
Análisis multivariable 20% riesgo SRE p<0,025
30% riesgo SRE en mts líticas p<0,01
Zoledrónico vs Pamidronato
Rosen 2003
Denosumab Zoledronico
Primeros SRE 315/1065 372/1040 NNT 16
Ptes con primer SRE 31% 36% P=0.006
Ptes >2 SRE 36% 44% P=0.021
RT sobre hueso 8% 12% HR 0.74; p=0.012
Hipercalcemia 28 ptes 58 ptes HR 0.48; p=0.035
Cirugía ósea 1% 1% NS
Mejora QOL 34% 31%
Martin M. 2012
FASE III Zoledrónico Denosumab
Reacciones agudas 27.3% 10.4%
Toxicidad renal 8.5% 4.9%
Hipocalcemia 3.4% 5.5%
Dolor dental 3.7% 5.6%
Osteonecrosis M 1.4% 2.0%
Stopeck 2010 y 2016
FASE EXTENSIÓN DenoDeno ZolDeno
Hipocalcemia 4,3% 3.1%
Osteonecrosis M 6.9% 5.5%
Dhesy-Thind S. 2017
• Zoledronic should be considered as adjuvant therapy for postmenopausal
patients who are deemed candidates for adjuvant systemic therapy.
• Risk factors for ONJ and renal impairment should be assessed.
• Data for adjuvant denosumab look promising but are currently insufficient
to make any recommendation.
Adjuvant bisphosphonate treatment in early breast cancer (EBCTCG)
EBCTCG 2015
Bone recurrence rate/year
POSTMENOPAUSAL
Death Rates POSTMENOPAUSAL
Recurence outside bone
POSTMENOPAUSAL
Evento Poblacion N OR p
Recidiva ósea Global 18.766 0.83 0.004
Recidiva ósea PostM 11.767 0.72 0.0002
Recidiva no-ósea PostM 11.767 0.82 0.0003
Mortalidad PostM 11.767 0.82 0002
Adjuvant denosumab in breast cancer (ABCSG-18): A randomised, double-blind, placebo controlled Trial
Gnant 2015
n: 3420
n: 1711
n: 1709
Gnant 2015
ABCSG-18: denosumab significantly delayed time to first clinical fracture vs placebo
HR = 0.50 (95% CI: 0.39–0.65) P < 0.0001
Percentage risk of fracture
Placebo
Denosumab
36 30 42 12 6 18 24 0 0
5
10
15
20
25
30
Ris
k o
f fr
ac
ture
(%
)
48
Months since randomisation
54 60 66 72
Number at risk
Placebo 1709 1660 1470 1265 1069 921 785 637 513 384 275 185 112
Denosumab 1711 1665 1488 1297 1118 965 823 688 549 432 305 221 116
Overall cumulative incidence of first clinical fractures
Placebo: n = 176
Denosumab: n = 92
Placebo 203/1709
Number of
events/patients
HR (95% CI)
vs placebo
92.6%
86.8%
80.4%
93.8%
88.9%
83.5%
167/1711 0.816 (0.66–1.00)
0.0510 Log-rank
Denosumab
P-value
Time since randomisation (months)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Dis
ea
se-f
ree
su
rviv
al
(%)
0
60
70
80
90
100
0.0515 Cox
Denosumab
Placebo
ABCSG-18: DFS (ITT analysis*)
Gnant 2015
ITT analysis consitent with sensitivity analysis in which pts switching to another bone-active treatment were censored - HR denosumab vs placebo 0.07 (95% CI 0.66-0.99; p=0.042)
RANK and RANKL link female sex hormones to BRCA1 mutation-induced breast cancer
• Preclinical studies have linked BRCA1 mutation mediated tumourigenesis to female sex hormones.
• Epidemiological studies suggest that early pregnancies do not confer reduced BC risk in BRCA1-mut carriers.
• Prophylactic salpingo-oophorectomy significantly reduces BC risk in BRCA1-mutation carriers.
Kumel S 2017
Las metástasis óseas son frecuentes y causan morbilidad en cáncer de mama
Denosumab es superior a Zoledrónico en retrasar el primer y sucesivos SRE
Menos rx infusionales y nefrotoxicidad
Denosumab reduce el riesgo de fractura en postmenopausicas que reciben IAs adyuvante… … pero no está plenamente esclarecido su papel como tto adyuvante
Se estudia el bloqueo de RANK-L como prevención del cáncer de mama BRCA1