Heterogeneidad, clonalidad y subclonalidadDr. Ignacio Gil Bazo
Director, Departamento de OncologíaClínica Universidad de Navarra
Pamplona
• Consultor/Asesor:
Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Roche
• Formador:
AstraZeneca, BMS, Guardant Health, MSD, Roche
Conflictos de Interés
• Introducción a la heterogeneidad, clonalidad y subclonalidad tumoral
• Heterogeneidad y terapias dirigidas: El cáncer de pulmón como ejemplo
• La biopsia líquida como posible solución
• Heterogeneidad e inmunoterapia
• Conclusiones
Índice
Jamal-Hanjani M, et al. NEJM 2017
Genomic Heterogeneity & survival
There was no significant association between the proportion of subclonal mutations and relapse-free survival (P = 0.70), but patients who had tumors with a high proportion of subclonal copy-number alterations were at significantly higher risk for
recurrence or death than those with a low proportion (P = 4.4 x 10−4).
Courtesy of Prof. Christian Rolfo, University of Maryland
PFS 6 monthsosimertinibstart
osimertinib + crizotinib start
EGFR L858R 37.1%
EGFR T790M 15.8%
TP53 Splice Site
SNV12.5%
BRCA1 D2N 8.9%
TP53 V272M 0.1%
EGFR Amplification ++
MET Amplification ++
AR Amplification +
20.0%
ND
8.4%
5.7%
ND
+
+++
ND
TP53 C176F 36.9%
RB1 R763* 22.7%
CDKN2A A57S 19.0%
PTEN S287* 8.6%
MET E859* 14.7%
MET Q714E 7.1%
AR S29R -
NOTCH1 -
FGFR1 AMP +++
MYC AMP ++
RAF1 AMP ++
BRAF AMP +
CDK6 AMP ND
3.9%
2.2%
2.0%
0.6%
1.1%
1.1%
-
-
ND
ND
ND
ND
ND
2.6%
1.3%
1.2%
0.4%
1.1%
0.9%
0.1%
-
ND
ND
ND
ND
ND
12.2%
6.0%
5.3%
2.0%
2.9%
2.7%
-
0.2%
++
ND
ND
ND
ND
16.4%
7.7%
8.2%
2.9%
ND
3.2%
-
ND
++
ND
+
ND
+
Pazopanibstart
Courtesy of Prof. Christian Rolfo, University of Maryland
Reduction of lung tumour mass more than 50% with complete resolution of symptomatology (ECOG PS 0).
CT scan after 2 months of pazopanib treatment
Baseline CT scan
Courtesy of Prof. Christian Rolfo, University of Maryland
Guo, et al. J Immunotherapy, 2019; Shong, et al. Lung Cancer, 2016
PD-L1 expression is induced by Chemotherapy
The impact of low and high intratumor heterogeneity (ITH) on clonal ancestry,
neoantigen clonality and T cell responses
Fennemann et al, Front Immunol, 2019
Male, 50 y-o, Lung Adenocarcinoma (TTF1 +, PDL-1: 95%), T1 N2 M1c, EGFR y ALK WT
15/01/2018
16/04/2018
16/04/2018
Male, 50 y-o, Lung Adenocarcinoma (TTF1 +, PDL-1: 95%), T1 N2 M1c, EGFR y ALK WT
15/01/2018
01/05/2018
16/04/2018
Male, 50 y-o, Lung Adenocarcinoma (TTF1 +, PDL-1: 95%), T1 N2 M1c, EGFR y ALK WT
16/04/2018
Starts on Crizotinib
Male, 50 y-o, Lung Adenocarcinoma (TTF1 +, PDL-1: 95%), T1 N2 M1c, EGFR y ALK WT
16/04/2018
January 2019
• Los tumores son heterogéneos y presentan una evolución clonal
• Este fenómeno es causa frecuente de resistencia al tratamiento dirigido
• La biopsia líquida nos permite conocer dicha evolución y tomar
decisiones terapéuticas
• Dicha heterogeneidad no solo ocurre en el tumor sino también en el
microambiente tumoral y tiene impacto en la respuesta a inmunoterapia
• La rebiopsia tisular o la biopsia líquida son mandatorias a la progresión
Conclusiones