1660P - ATM role in Prostate Cancer (PrCa) progression and survival

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Prostate Cancer
Genitourinary Cancers
Translational Research
Presenter Ylenia Cendón Flórez
Citation Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390
Authors Y. Cendón Flórez1, P. Nombela Blanco2, A. Medina3, N. Romero Laorden2, J. Puente4, P.P. López Casas5, A. Gutierrez Pecharromán6, R. Sanchez-Escribano7, L. Magraner2, E. Gallardo Diaz8, N. Lainez9, P. Jiménez Gallego10, R. Lozano Mejorada11, E. Almagro Casado12, R. Luque Caro13, M. Domenech14, A. Hernández Jorge15, E. Castro Marcos1, M.D.P. González-Peramato Gutierrez16, D. Olmos Hidalgo17
  • 1Prostate Cancer Unit, CNIO- Spanish National Cancer Center, 28029 - Madrid/ES
  • 2Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, 28029 - Madrid/ES
  • 3Medical Oncology, Centro Oncológico de Galicia, A Coruña/ES
  • 4Medical Oncology, Hospital Clinico Universitario San Carlos, 28040 - Madrid/ES
  • 5Clinical Research, CNIO- Spanish National Cancer Center, 28029 - Madrid/ES
  • 6Pathology Department, Hospital Universitario de Móstoles, 28935 - Móstoles/ES
  • 7Medical Oncology, Hospital Universitario de Burgos, Burgos/ES
  • 8Medical Oncology, Hospital de Sabadell Corporacis Parc Tauli, 8208 - Sabadell/ES
  • 9Medical Oncology, Complejo Hospitalario de Navarra, 31008 - Pamplona/ES
  • 10Medical Oncology, , Hospital Universitario de Gran Canaria Dr Negrín, 35010 - Las Palmas de Gran Canaria/ES
  • 11Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid/ES
  • 12Medical Oncology, Hospital Universitario Quirón Salud, Madrid/ES
  • 13Medical Oncology, HOSPITAL VIRGEN DE LAS NIEVES, Granada/ES
  • 14Medical Oncology, Hospital Althaia, Manresa/ES
  • 15Medical Oncology, Onkologikoa, 20014 - Donostia/ES
  • 16Pathology Department, Hospital La Paz, 28029 - Madrid/ES
  • 17Prostate Cancer Clinical Cancer Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid/ES

Abstract

Background

Germline and/or somatic aberrations in ATM gene have been recently identified in up to 5% of PrCa cases. It has been also described that mutations in DNA repair genes predispose individuals to more aggressive and lethal phenotypes. For these reasons, our goal is to investigate the role of ATM in PrCa progression.

Methods

To study the cooperation of Atm in prostate cancer progression in vivo, we crossed the transgenic mouse model TRAMP with Atm null mice in C57BL/6 background. This model allows us to elucidate the progression of prostate cancer in wild-type (+/+), heterozygous (+/-), and homozygous (-/-) Atm loss in mice. PIN, invasive and metastatic prostate cancer as well as survival curves were compared for the three arms. In addition, in a large cohort of mCRPC (n = 419) from the prospective PROREPAIR-B study (NCT03075735), in which a large panel of germline DNA repair genes were studied, we compared the clinico-pathological characteristics at baseline and mCRPC diagnosis between germline ATM mutation carriers and non-ATM carriers. Chi-Square and Exact Fisher test, the Kaplan-Meier method and Long-rank test were used for statistical analyses.

Results

Twenty eight TRAMP(T/+); Atm(+/+) and 45 TRAMP(T/+); Atm(+/-) mice were follow-up until sacrifice-endpoint. Heterozygous Atm loss mice presented higher frequency of metastasis in the necropsy compared to Atm wild-type (44% vs. 21%, p = 0,045) and shorter median survival (26 vs. 32 weeks, p = 0,008). There were not significant different observed in PIN or invasive tumour prevalence. TRAMP(T/+); Atm(-/-) mice were excluded from analyses due to the early development of lethal thymomas requiring sacrifice before week 16. On the other hand, 8 patients out of 419 were found to harbour germline pathogenic ATM mutations (1.9%), and compared with non-ATM carriers presented higher frequency stage IV at diagnosis (63% vs. 34%, p = 0.2), bone metastasis (100% vs. 82%, p = 0.4) without other relevant differences found in these preliminary analyses.

Conclusions

Aberration in the ATM gene may favour metastatic progression in PrCa in prostate cancer preclinical models, although its clinical implication will require further clarification in the future.

Clinical trial identification

Part of the results came from the prospective PROREPAIR-B study (NCT03075735)

Legal entity responsible for the study

Spanish National Cancer Research Centre

Funding

Prostate Cancer Unit-Spanish National Cancer Research Centre

Disclosure

All authors have declared no conflicts of interest.