En la vanguardia de la oncologa traslacional Avances

En la vanguardia de la oncología traslacional Avances en prevención y diagnóstico precoz José Luis Pérez Gracia Departamento de Oncología Clínica Universidad de Navarra 10 de mayo de 2019 1

Disclosures • Research grants and support: Roche, BMS, MSD, Ipsen, Eisai • Speakers bureau and advisory boards: Roche, BMS, MSD, Ipsen, Eisai • Travel grants: Roche, MSD, BMS

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Detección precoz / prevención: • Población diana: población general o individuos con mayor riesgo • • • Objetivo de la intervención: radical • Mayor eficacia y mejor coste eficacia (? ) • Ventana de intervención: amplia • Diseño de estudios: • • • Keith, Nature Rev Clin Oncol 2013 Toxicidad / morbilidad de tratamientos y pruebas Adherencia a los programas • ¿Objetivo? Especificidad y sensibilidad Competencia / colaboración entre diferentes estrategias Diferente perfil molecular del tumor y del microambiente

Gerlinger, NEJM 2012

Immunosurveillance Dunn, Immunity 2004

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Giorgios and Andromache Papanikolau Papanicolaou GN. New cancer diagnosis. In: Proceedings of the Third Race Betterment Conference, 1928 2 -5 Jan; Battle Creek, Michigan: 528 -34. Siegel, Ca Cancer J Clin 2019

Teixeira, Janes, et al Nature Med 2019

Gene expression and Methylation profiles of regressive and progressive CIS lesions Genomic aberrations in pre-invasive lung lesions a: mutation frequencies (TCGA) b: copy number (TCGA) c: copy number (CIS) d: mutation frequencies (CIS) Teixeira, Janes, et al Nature Med 2019

Immunofluorescent staining demonstrating the increased MKI 67 and KRT 5 staining and reduced TUB 1 A 1 staining in the Proliferative subtype Genes (n =3936) organized into nine gene co-expression modules Bubbleplots showing significant associations between molecular subtypes and clinical variables Beane, Spira, et al Nature Comm 2019

Top panels: progressive severe dysplasia: reduced presence of immune cells (M 2 macrophages (CD 68/163) CD 8 T cells Bottom panels: regressive moderate dysplasia: increased presence of immune cells Boxplots of the percentages of CD 68 and CD 163, CD 68, CD 163, CD 4, and CD 8 positively stained cells between progressive/persistent and regressive biopsies Dashed yellow line: separation of epithelium and stromal compartments. Beane, Spira, et al Nature Comm 2019

Driver mutations in normal airway epithelium elucidate spatiotemporal resolution of lung cancer T: tumor S: tumor adjacent small airways L: distant large airways Na: nasal epithelium N: uninvolved normal lung tissue Field cancerization: observations of histological abnormalities in tumor‐adjacent normal tissues Kadara, Scheet et al, Am J Resp and Crit Care Med 2019 (in press)

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

MMS: CA 125 +/‐ ecografía Jacobs and Skates, Lancet 2016

Guo, abstract 912, AACR 2019

Selected abstracts on early detection, AACR 2019 Poster #, presenter Biomarker / method Clinical setting Outcome 914, Cani TMPRSS 2: ERG and PCA 3 RNA / Mi. Prostate Score (Mi. PS) combined with PSA and digital rectal exam Primary diagnosis of prostate cancer Improved early detection of aggressive prostate cáncer vs benign hiperplasia or low grade cancer 918, Dominguez Machine learning based upon flow cytometry immunophenotyping of myeloid‐derived suppressor cells and lymphocyte cell populations Primary diagnosis of prostate cancer 90% sensitivity for predicting if subjects should undergo biopsy (aggressive prostate cancer vs lower‐ grade PC or benign prostatic hyperplasia 916, Kim Machine learning model trained on cell‐free DNA profiles from cancer patients / targeted assay of somatic, methylation and epigenomic variants Primary diagnosis of colorrectal cancer 94% detection of early stage CRC 917, Manjunath CTCs enriched by microfilter isolation and immunofluorescence staining for cytokeratin, Ep. CAM, CD 14/45, PD‐L 1, vimentin, N‐cadherin. Characterization of pulmonary nodules on screening Improved cancer diagnosis 4128, Kammer Known serum proteins / Compensated Interferometric Reader (CIR, diode laser, capillary and CCD) Indeterminate pulmonar nodules Correct classification of patients in the intermediate risk group in both the training and validation cohorts. 4126, Vazquez‐ Sanchez Microbiota / Sequencing of the 16 S ribosomal RNA V 4 region (Illumina) Cervical / anal HPV infection Enrichment of Ureaplasma and Prevotella (cervical HPV) and Peptinophilus was associated (anal HPV) 4219, Sadhasivam Mitochondrial damage / Long‐run real‐time PCR‐based DNA‐damage quantification (LORDQ) assay Cervix dysplasia Correlation with presence / absence of dysplasia 913, Christensen Circulating tumor DNA (16 patient specific somatic tumor mutations) / multiplex PCR and ultra‐deep sequencing Relapse of muscle invasive bladder cancer 92% identification of metastatic relapse (100% specificity). Lead‐time over radiology: 100 days (range: ‐ 17‐ 245 days).

Sine, Carrascosa and Trau, Nature Comm 2018

Sine, Carrascosa and Trau, Nature Comm 2018

Sine, Carrascosa and Trau, Nature Comm 2018

Sine, Carrascosa and Trau, Nature Comm 2018

Cell-lines Patients Sine, Carrascosa and Trau, Nature Comm 2018

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Figure 2: Heat map generated by unsupervised hierarchical clustering of extracted radiomic features, applied to separate (a) training and (b) test sets of screening sample for phenotype identification Contos and Vachon, Radiology 2019

Contos and Vachon, Radiology 2019

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Global survival and survival free from hepatocarcinoma (no cirrhosis) Global survival and survival free from hepatocarcinoma (cirrhosis) Felds, Zeuzem et al, NEJM 2015 Carrat, Pol et al, Lancet 2019

Marcellin, Heathcote et al, Lancet 2013 Chang, Chen et al, Gastroenterology 2016 Hosaka, Kumada et al, Hepatology 2013

The Polaris Observatory, Lancet Gastroenterol Hepatol 2018

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Thompson and Ford, NEJM 2013

Exceptional activity of ARN-509 (apalutamide) in prostate cancer prevention in rats Murillo, abstract 2730, AACR 2019

Exceptional activity of ARN-509 (apalutamide) in prostate cancer prevention in rats Murillo, abstract 2730, AACR 2019

Phosphodiesterase 10 A inhibitor MCI-048 suppresses urethane and NNK mouse models of induced lung tumorigenesis • Phosphodiesterases are critical regulators of a myriad of physiological and pathological processes through hydrolysis and control of intracellular levels of c. AMP and c. GMP to 5_AMP and 5_GMP (Azevedo, Endocr Rev 2014) – PDE 10 A expression correlates with lung cancer prognosis and its pharmacological blockade inhibitis growth of NSCLC cell lines and tumorigenesis (Shen, Am J Hum Genet 2017, Zhu, Oncotarget 2017 – PD 10 A blockade inhibits colon cancer cell growth and colon tumorigenesis (Lee Oncogene 2015 and Nicotine-derived Nitrosamine Ketone Oncotarget 2015) Zhu, Piazza, et al, abstract 2731 AACR 2019

Phosphodiesterase 10 A inhibitor MCI-048 suppresses urethane and NNK mouse models of induced lung tumorigenesis Zhu, Piazza, et al, abstract 2731 AACR 2019

Fusco and Perez-Gracia, Cancer Medicine 2018

SNPs validated SNP rs 12660420 rs 6835978 Chromosome Position Reference Alternate 6 4 166193932 47500814 C A Study P-value MAF OR 95% CI T Discovery Validation Combined 1. 48 E‐ 04 0. 04 5. 66 E‐ 05 0. 28 0. 32 0. 31 5. 29 1. 88 2. 80 2. 24 ‐ 12. 51 1. 01 ‐ 3. 5 1. 69 ‐ 4. 61 G Discovery Validation Combined 3. 69 E‐ 04 0. 04 1. 02 E‐ 04 0. 24 0. 32 0. 31 5. 15 1. 80 2. 57 2. 09 ‐ 12. 7 1. 02 ‐ 3. 19 1. 6 ‐ 4. 1 • rs 12660420 (locus 6 q 27): non-coding transcript of PDE 10 A gene (phosphodiesterase 10 A) • rs 6835978 (locus 4 p 12): intronic variant of gene ATP 10 D (ATPase transporter of phospholipids 10 D) Fusco and Perez-Gracia, Cancer Medicine 2018

Correlation of PDE 10 A protein expression with OS and PFS in stage I-II NSCLC patients (n=149) Fusco and Perez-Gracia, Cancer Medicine 2018

Selected abstracts on Chemoprevention, AACR 2019 Poster #, presenter Chemopreventive agent Setting Outcome 5066, Kim HJC 0152 (inhibitor of STAT 3, regulator of energy metabolism via transcriptional induction of HIF‐ 1α) Mouse models of estrogen receptor negative breast cancer Reduces and prevents mammary tumor development 5071, Parris Palbociclib, CDK 4/6‐Cyclin D inhibitor MTV‐erb. B 2 transgenic mice, with stemness of mammary epithelial cells in premalignant tissues Inhibition of mammary stemness in the premalignant tissues through reprogramming of mammary epithelial cells 5072, Mazumdar Everolimus p 53 -null mammary gland, BRCA 1 and MMTV-erb. B 2 mice Reduced tumor development 5074, Ahmetmursel Sulindac + Erlotinib Apc‐mutant polyposis in rat colon (Pirc) model p. ERK inhibition and reduced polyp development 5075, Kumar Naproxen Transgenic Kras. G 12 V mice Reduced progression of adenomas to lung tumors: 52% decrease in lung tumors with similar number of adenomas 5087, Chen Carvedilol Mouse epidermal JB 6 P+ cells subjected to ultraviolet ray exposure and H 2 O 2 Carvedilol has preventive activity against ultraviolet radiation 3864, Ward MCI‐ 030, PDE 10 A inhibitor Apc+/min‐FCCC mouse model Inhibits colon tumor formation

Avances en prevención y diagnostico precoz • Introducción • Avances en diagnóstico precoz • Biomarcadores de proximidad • Biomarcadores sistémicos • Estudios de imagen • Avances en prevención • Control de factores de riesgo • Quimioprevención • Cáncer hereditario • Conclusiones

Robert W. Miller (1921‐ 2006) Miller, NEJM 1968 Li and Fraumeni, JNCI 1969 David Malkin, Science 1990 Frederick Li (1940‐ 2015) and Joseph Fraumeni (1933‐)

Nuevos desarrollos en p 53 • Caracterización de nuevas variantes (abstracts 1717, 4159) y de la biología molecular (2032, 3666, 4512, 4627) • Mejoras en la estrategia de seguimiento y tratamiento (979, 1639, 2406, 2434, 3316) • Inhibición de la oncogénesis: – Prevención de la pérdida de heterozigosidad (LOH) – Reactivación de células p 53 mutadas a p 53 “wild-type”

control treated Rotter, AACR 2019 Tal, Rotter, Oncotarget 2016

Conclusiones • El desarrollo de la biología molecular también se extiende al diagnóstico precoz y a la prevención del cáncer • Estos desarrollos se traducirán en avances clínicos que modularán la presentación y las características de los pacientes con cáncer

En la vanguardia de la oncología traslacional Muchas gracias por vuestra atención jlgracia@unav. es 46