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