Association between BRCA2 alterations and intraductal and cribriform histologies in prostate cancer

Rebeca Lozano, Daniela C. Salles, Shahneen Sandhu, Isabel M. Aragón, Heather Thorne, Fernando López-Campos, José Rubio-Briones, Ana M. Gutierrez-Pecharroman, Laneisha Maldonado, Tomas di Domenico, Alejandro Sanz, Juan D. Prieto, Isabel García, María I. Pacheco, Teresa Garcés, Casilda Llacer, Nuria Romero-Laorden, Francisco Zambrana, Pedro P. López-Casas, David LorenteJoaquin Mateo, Colin C. Pritchard, Emmanuel S. Antonarakis, David Olmos, Tamara L. Lotan, Elena Castro

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of genetic testing for patients with IDC in the primary tumour. Patients and methods: To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case–control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression models were constructed to identify independent factors associated with both histology patterns. Results: No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1–16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1–13.1). CRIB morphology was also independently associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7–19.3). Conclusions: While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies, independently of other clinical-pathologic factors.

Original languageEnglish (US)
Pages (from-to)74-83
Number of pages10
JournalEuropean Journal of Cancer
Volume147
DOIs
StatePublished - Apr 2021
Externally publishedYes

Bibliographical note

Funding Information:
C.L. declares honoraria from Roche and travel support from Astellas Pharma and Angelini. N.R-L. declares speaker fees from MSD, consulting or Advisory Role from Ipsen, Astellas Pharma, Bayer, Tesaro, AstraZeneca and Sanofi, research funding from Janssen (Inst), and Pfizer (Inst) and travel support from Janssen.

Funding Information:
‘ Instituto de Salud Carlos III ’ supported RL ( CM17-00221 ), NRL ( JR17/00007 ), CL ( CM19/00234 ) and EC ( JR18/00011 ) and ‘ Ministerio de Ciencia e Innovación’ provided funding to IMA ( FJCI-2016-28121 ), DO ( RYC-2015-18625 ) and EC ( JCI-2014-19129 ). The Prostate Cancer Foundation Young Investigator Award program has supported CC, JM, ESA, DO, TL and EC. CCP ESA is partially supported by NIH grant R01CA185297 , DOD grant W81XWH-16-PCRP-CCRSA , the Prostate Cancer Foundation , and the Patrick C. Walsh research fund .

Funding Information:
S.S. declares honoraria from Amgen, Bristol-Meyers Squibb, Merck, Merck Serono consulting or Advisory Role from AstraZeneca and Merck, research funding from AstraZeneca, Merck Sharp and Dohme, Amgen and Endocyte.F.L-C. declares consulting or Advisory Role from Astella Pharma, speaker fees from Janseen, Astellas Pharma, Research Funding from Astellas Pharma (Inst) and travel support from Astellas Pharma and Janssen.J.R-B. declares consulting or Advisory Role from Janssen, Astellas Pharma and Bayer, and Research Funding from HealthMDx (Inst).J.R.B declares consulting or advisory role from Astellas Pharma, Bayer and Janssen-Cilag and research funding from MDxHealth (Inst).C.L. declares honoraria from Roche and travel support from Astellas Pharma and Angelini. N.R-L. declares speaker fees from MSD, consulting or Advisory Role from Ipsen, Astellas Pharma, Bayer, Tesaro, AstraZeneca and Sanofi, research funding from Janssen (Inst), and Pfizer (Inst) and travel support from Janssen.E.S.A. declares honoraria and consulting or advisory role from Astellas, AstraZeneca, Clovis Oncology, Dendreon, ESSA, Janssen Biotech, Medivation, Merck, Sanofi; Research Funding from Aragon Pharmaceuticals (Inst), Astellas (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst), Dendreon (Inst), Exelixis (Inst), Genetech (Inst), Janssen Biotech (Inst), Johnson&Johnson (Inst), Merck (Inst), Millennium (Inst), Novartis (Inst), Sanofi (Inst) and Tokai pharmaceuticals (Inst); co-inventor of a biomarker technology licensed to Qiagen.D.O. declares honoraria from Bayer, Janssen and Sanofi, consulting or Advisory Role from AstraZeneca, Bayer, Clovis, Daiichi-Sankyo, Janssen, MSD and Roche, research funding from Astellas (Inst), AstraZeneca (Inst), Bayer (Inst), Genentech (Inst), Janssen (Inst), Medivation (Inst), MSD (Inst), Pfizer (Inst), F. Hoffman-Roche (Inst) and Tokai Pharmaceutics (Inst) and travel support from Bayer, Ipsen, Janssen and Roche.T.L. declares consulting or advisory role for Janssen and research funding from DeepBio and Ventana Medical Systems.E.C. declares honoraria from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer and Roche, consulting or Advisory Roles for AstraZeneca, Bayer, Janssen, MSD and Pfizer, research funding from AstraZeneca (Inst), Bayer (Inst) and Janssen (Inst) and travel support from Astra Zeneca, Bayer and Janssen.This study was supported by grants from ?Instituto de Salud Carlos III? (PI19/01475 to EC; PI13/01287, PI16/01565 and PI19/01380 to DO), ?Fundaci?n Cient?fica de la AECC? research grant (PROYE19054OLMO to DO) and an unrestricted grant from ?Fundaci?n CRIS contra el C?ncer?. Data used in this study were also generated as part of a Department of Defense awards W81XWH-18-1-0756 (PC170510) and W81XWH-18-1-0356 (PC170503P2) to CCP, W81XWH-18-1-0758(PC170510P1) to JM, and W81XWH-18-1-0770 (PC170510P2) to DO. ?Instituto de Salud Carlos III? supported RL (CM17-00221), NRL (JR17/00007), CL (CM19/00234) and EC (JR18/00011) and ?Ministerio de Ciencia e Innovaci?n? provided funding to IMA (FJCI-2016-28121), DO (RYC-2015-18625) and EC (JCI-2014-19129). The Prostate Cancer Foundation Young Investigator Award program has supported CC, JM, ESA, DO, TL and EC. CCP ESA is partially supported by NIH grant R01CA185297, DOD grant W81XWH-16-PCRP-CCRSA, the Prostate Cancer Foundation, and the Patrick C. Walsh research fund.

Funding Information:
This study was supported by grants from ‘ Instituto de Salud Carlos III ’ ( PI19/01475 to EC; PI13/01287 , PI16/0156 5 and PI19/01380 to DO), ‘ Fundación Científica de la AECC’ research grant ( PROYE19054OLMO to DO) and an unrestricted grant from ‘ Fundación CRIS contra el Cáncer’ . Data used in this study were also generated as part of a Department of Defense awards W81XWH-18-1-0756 (PC170510) and W81XWH-18-1-0356 (PC170503P2) to CCP, W81XWH-18-1-0758(PC170510P1) to JM, and W81XWH-18-1-0770 (PC170510P2) to DO.

Funding Information:
T.L. declares consulting or advisory role for Janssen and research funding from DeepBio and Ventana Medical Systems .

Funding Information:
S.S. declares honoraria from Amgen, Bristol-Meyers Squibb, Merck, Merck Serono consulting or Advisory Role from AstraZeneca and Merck, research funding from AstraZeneca , Merck Sharp and Dohme , Amgen and Endocyte .

Funding Information:
J.R.B declares consulting or advisory role from Astellas Pharma, Bayer and Janssen-Cilag and research funding from MDxHealth (Inst).

Funding Information:
E.C. declares honoraria from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer and Roche, consulting or Advisory Roles for AstraZeneca, Bayer, Janssen, MSD and Pfizer, research funding from AstraZeneca (Inst), Bayer (Inst) and Janssen (Inst) and travel support from Astra Zeneca, Bayer and Janssen.

Funding Information:
D.O. declares honoraria from Bayer, Janssen and Sanofi, consulting or Advisory Role from AstraZeneca, Bayer, Clovis, Daiichi-Sankyo, Janssen, MSD and Roche, research funding from Astellas (Inst), AstraZeneca (Inst), Bayer (Inst), Genentech (Inst), Janssen (Inst), Medivation (Inst), MSD (Inst), Pfizer (Inst), F. Hoffman-Roche (Inst) and Tokai Pharmaceutics (Inst) and travel support from Bayer, Ipsen, Janssen and Roche.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • BRCA2
  • Cribriform
  • Germline testing
  • Intraductal
  • Prostate cancer

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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