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

Introducción a la heterogeneidad, clonalidad y

subclonalidad tumoral

Turajlic S, et al. Nat Rev Gen 2019

Modes of cancer evolution: Following the Darwinian rules

Easwaran et al. Molecular Cell, 2014

Clonal Evolution in Cancer

Burrell et al. Mol Oncol, 2014

Heterogeneidad y terapias dirigidas:

El cáncer de pulmón como ejemplo

Koshaka et al. Fut Oncol, 2019

Clonal Evolution in NSCLC

Koshaka et al. Fut Oncol, 2019

Clonal Evolution in EGFR + NSCLC

Wang et al. J Hematol Oncol, 2016

Clonal Evolution in EGFR + NSCLC

Jamal-Hanjani M, et al. NEJM 2017

Tracking the Evolution of NSCLC: the TRACERx Consortium

Jamal-Hanjani M, et al. NEJM 2017

TRACERx Consortium: clinical questions

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).

Jamal-Hanjani M, et al. NEJM 2017

Timing of Somatic Events in NSCLC Evolution

La biopsia líquida como posible solución

Pantel K, ASCO, 2018

The Concept of Liquid Biopsy in Cancer

Amirouchene-Angelozzi et al. Cancer Discovery, 2017

Tumor evolution as a therapeutic target

Turajlic S, et al. Nat Rev Gen 2019

Clonal Evolution of Treatment Resistance

PFS 7 monthsosimertinib start switch to afatinib

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

Turajlic S, et al. Nat Rev Gen 2019

Clonal Evolution of Treatment Resistance

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

Heterogeneidad e inmunoterapia

Sharma P, et al. Cell, 2016

Dynamic profile of the resistance factors to IO

Sharma P, et al. Cell, 2016

Dynamic profile of the resistance factors to IO

Wilmott JS, et al. Clin Cancer Res, 2017

Dynamic profile of the resistance factors to IO

Zaretsky JM, et al. New England J Med, 2016

Dynamic profile of the resistance factors to IO

Munari E, et al. JTO 2018

Intra-tumor heterogeneity of PD-L1 expression

Hong L, et al. ASCO 2019

Spatial and Temporal Heterogeneity of PD-L1 in NSCLC

Fournel, et al. Cancer Letters, 2019

Is PD-L1 expression inducible?

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

Hyperprogression not only a natural history …

Lo Russo et al. Clin Cancer Res, 2019

Rossi et al. Crit Rev Oncol Hematol, 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

Conclusiones

• 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