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Factores pronósticos y
predictivos en cáncer de
pulmón no microcítico.
Dr. Hernando Rodríguez Ramírez.
HOSPITAL CLINICO LOZANO BLESA
ZARAGOZA
Independent of treatment
Survival Staging
PS
Factores pronósticos clínicos
J Thorac Oncol. 2010;5(5):620.
Survival by Pathologic Stage: IASLC
New Classification
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thoracic Oncol. 2007;2:706-714.
0 2 4 8 10 0
20
100
Pati
en
ts (
%)
6
40
60
80
Survival Yrs
IA
IB
IIA
IIB
IIIA
IIIB
IV
1168/3666
1450/3100
1485/2579
1502/2252
2896/3792
263/297
224/266
119
81
49
31
22
13
17
73
58
46
36
24
9
13
5-Yr, % MST Deaths/N
UV light
mRNA measure
Endonucleasa
ERCC1
Factores moleculares
2006
IALT: Prognostic and Predictive
Value of ERCC1 in Adjuvant
Treatment of NSCLC
1. Olaussen KA, et al. N Engl J Med. 2006;355:983-991. Copyright © 2006 Massachusetts Medical Society.
All rights reserved. 2. Soria JC, et al. ESMO 2008. Abstract 235PD.
GILT STUDY
0.6
P = .002
Resected NSCLC
Stage IV NSCLC gem/cis
High RRM1
Low RRM1
Low RRM1
High RRM1
RRM1 as a prognostic marker
in surgically resected NSCLC[1]
RRM1 as a predictive marker
for chemotherapy survival in
advanced NSCLC[2]
RRM1: A Prognostic and
Predictive Biomarker for DFS
1. Bepler G, et al. J Clin Oncol. 2004;22:1878-1885. Reprinted with
permission. © 2008 American Society of Clinical Oncology. All rights
reserved.
2. Rosell R, et al. Oncogene. 2003;22:3548-3553. Reprinted by
permission from Macmillan Publishers Ltd: [JOURNAL NAME] (reference
citation), copyright (year of publication).
P = .003
0
25
50
75
100
Su
rviv
al (%
)
0 20 40 60 80 100 120 Mos
0
0.2
0.8
1.0
Pro
ba
bil
ity
0 20 40 60 80 100 120 Mos
0.4
Breast cancer susceptibility gene 1
(BRCA 1)
Bajo niveles de expresión del m RNA asociado a larga supervivencia.
Altos niveles a baja supervivencia.
Resistencia al platino, etoposido.
Respuesta a los a antimicrotúbulos. (taxanos y vinorelbina).
Med Oncol (2012) 29:1599–1605
BRCA -1 complex
LOW RAP y cualquier expresión
de BCRA1
Low BRCA1 o intermedio/ o alto o intermedio de RAP80
•NON-SQUAMOUS CARCINOMA
•SQUAMOUS CARCINOMA HISTOLOGY
• EGFR Mutation
• ALK Translocation
• OTHERS
MOLECULAR PROFILE
Individualized Therapy
Cisplatin/Gemcitabine vs Cisplatin/
Pemetrexed in Advanced NSCLC
Overall, median OS for cisplatin/pemetrexed noninferior to cisplatin/gemcitabine: each 10.3 mos
HR: 0.94 (95% CI: 0.84-1.05)
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
0 6 12 18 30
0.2
0.4
0.6
0.8
1.0
Surv
ival Pro
bability
24
Survival Time (Mos) in Patients With Nonsquamous Histology
Adjusted HR: 0.81 (95% CI: 0.70-0.94)
CP CG
Median (95% CI)
CP vs CG
11.8 (10.4-13.2) 10.4 (9.6-11.2)
0 6 12 18 30
0.2
0.4
0.6
0.8
1.0
Surv
ival Pro
bability
24
Survival Time (Mos) in Patients With Squamous Cell Carcinoma
Adjusted HR: 1.23 (95% CI: 1.00-1.51)
CP CG
Median (95% CI)
CP vs CG
9.4 (8.4-10.2) 10.8 (9.5-12.1)
0 0
Molecular PROFILE
Driver mutationdruggable
targets
Incorporation of Molecular Profiling into Therapeutic
Decision-Making Process for Advanced NSCLC
• Who to test: Patients with NSCLC and adenocarcinoma component
• What to test for: EGFR mutation and ALK fusion (+ others?)
• What specimen: core needle biopsy (or multi-pass FNA), cytology cell block,
surgical biopsy (bone biopsy problematic)
• How to test: concurrently (not sequentially test-by-test)
• How long a turn-around time is acceptable?: 2 weeks or less
• When to test: at the time of diagnosis (not just when treatment decision
needed)
• When to re-test: after a targeted therapy intervention (to assess for tumor
evolution in the molecular profile)
General Guidelines for 2013
Adapted from: CAP/IASLC/AMP expert panel. Manuscript in preparation. Available at
http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf
EGFR mutations.
Imai and Takaoka Nature Reviews Cancer 6, 714–727 (September 2006) | doi:10.1038/nrc1913
Growth Differentation, survival Monomeric on cell surface
HER1 erbB-1
IPASS: PFS Overall and by EGFR
Mutation Status
Overall, PFS at 12 mos significantly greater with gefitinib vs carboplatin/ paclitaxel: 24.9% vs 6.7%, respectively
HR for progression or death: 0.74 (95% CI: 0.65-0.85; P < .001)
Mok TS, N Engl J Med. 2009;361:947-957. Copyright © 2009 Massachusetts Medical Society. All rights reserved.
EGFR Mutation Positive
HR: 0.48 (95% CI: 0.36-0.64; P < .001)
Pro
bability o
f PFS
Mos Since Randomization
Gefitinib Paclitaxel/ carboplatin
1.0
0.8
0.6
0.4
0.2
0 0 4 8 12 16 20 24
EGFR Mutation Negative
HR: 2.85 (95% CI: 2.05-3.98; P < .001)
Pro
bability o
f PFS
Mos Since Randomization
Gefitinib
Paclitaxel/ carboplatin
1.0
0.8
0.6
0.4
0.2
0 0 4 8 12 16 20 24
Events Gefitinib: 97 (73.5%) Pac/carbo: 111 (86.0%)
Events Gefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%)
IPASS: Survival Analysis
Median OS not significantly different between arms, both overall and in patients with or without EGFR mutations
Yang CH, et al. ESMO 2010. Abstract LBA2.
Population
Median OS, Mos
HR Gefitinib (n = 609)
Carboplatin/Paclitaxel
(n = 608)
Overall 18.8 17.4 0.90
EGFR mutation 21.6 21.9 1.00
No EGFR mutation
11.2 12.7 1.18
OPTIMAL: Erlotinib vs Gem/Carb in
Adv NSCLC With EGFR Mutations
Wang J, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2010. Abstract 18.
Chemo-naive patients
with advanced NSCLC,
ECOG PS 0-2, and
EGFR mutations
(N = 165)
Erlotinib 150 mg PO QD q3w for ≤ 4 cycles
(n = 83)
Gemcitabine 1000 mg/m2 on Days 1, 8 + Carboplatin AUC = 5 on Day 1
q3w for ≤ 4 cycles (n = 82)
Primary endpoint: PFS
Secondary endpoints: OS, safety, QoL, biomarker analysis
OPTIMAL: Erlotinib vs Gem/Carb
in Adv NSCLC With EGFR
Mutations—Results Erlotinib produced a nearly 3-fold improvement in median
PFS vs gemcitabine/carboplatin: 13.1 vs 4.6 mos, respectively
Striking increase in response rate: 83% with erlotinib vs 36% with gemcitabine/carboplatin
Toxicity better in erlotinib arm, except for rash and diarrhea
Fewer treatment related AEs (79.5% vs 94.4%)
Fewer serious AEs (all grades): 2.4% vs 13.9%
Fewer hematologic AEs: anemia (4.8% vs 72.2%), neutropenia (6.0% vs 68.1%), thrombocytopenia (3.6% vs 63.9%)
No unexpected AEs in either arm
Wang J, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2010. Abstract 18.
Factor pronóstico la mutación
EGFR?
Clin Transl Oncol (2010) 12:92-99
Lancet Oncol 2009; 10: 1001–10
INTACT TRIBUTE BR 21
8.3 meses vs 3.3 MESES
Hirsch F, et al. Clin Cancer Res. 2010;16:4909-4911.
Proposed Methods to Detect ALK-
Positive Patients
4 proposed methods of testing
FISH
IHC
Reverse transcriptase polymerase chain reaction
DNA sequencing
FISH IHC RT-PCR DNA Sequencing
J Clin Oncol 2013
CONCLUSIONES
El estudio de los factores predictores de respuesta nos ayuda a individualizar el tratamiento, seleccionando aquellos pacientes que se benefician de las terapias respecto a los que solo reciben toxicidad.
La mutación EGFR y la traslocación ALK nos ayuda a predecir que pacientes responden a la terapia dirigida.
Marcadores moleculares tipo ERCC1, RRM1, BRCA1 ayudan a predecir los que responderán a la quimioterapia ?
CONCLUSIONES
Los factores pronósticos y predictores mas prometedores requieren validación prospectiva en ensayos clínicos.
Gracias
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